TW200829258A

TW200829258A - Glucopyranosyl-substituted benzyl-benzonitrile derivatives, medicaments containing such compounds, their use and process for their manufacture

Info

Publication number: TW200829258A
Application number: TW096141737A
Authority: TW
Inventors: Frank Himmelsbach; Matthias Eckhardt; Peter Eickelmann; Leo Thomas
Original assignee: Boehringer Ingelheim Int
Priority date: 2006-11-06
Filing date: 2007-11-05
Publication date: 2008-07-16
Also published as: CA2668623A1; WO2008055870A8; WO2008055870A1; EP2079753A1; US20100069310A1; US7879806B2; AR063569A1; JP2010508371A; CL2007003187A1

Abstract

Glucopyranosyl-substituted benzyl-benzonitrile derivatives of general formula I as defined according to claim 1, including the tautomers, the stereoisomers thereof, the mixtures thereof and the salts thereof. The compounds according to the invention are suitable for the treatment of metabolic disorders.

Description

200829258 九、發明說明：【發明所屬之技術領域】本發明係關於通式1之經葡萄糠哌喃基取代之苄基苯甲腈衍生物：200829258 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a benzyl benzonitrile derivative substituted with a glucosinyl group of the formula 1:

R7a〇’、j^、〇R7< OR7b 其中基團R2至R6及R7a、R7b、R7e係如下文所定義，其包括其互變異構體、立體異構體、混合物及其鹽。本發明進一步係關於含有本發明之式I化合物之醫藥組合物以及本發明化合物用於製備用以治療代謝病症之醫藥組合物的用途。另外，本發明係關於用於製備本發明之醫藥組合物以及化合物之方法。【先前技術】在文獻中，提出將對鈉依賴性葡萄糖共轉運體SGLT2具有抑制作用的化合物用於治療疾病，尤其糖尿病。R7a〇', j^, 〇R7<OR7b wherein the groups R2 to R6 and R7a, R7b, R7e are as defined below, including tautomers, stereoisomers, mixtures thereof and salts thereof. The invention further relates to the use of a pharmaceutical composition comprising a compound of formula I of the invention and a pharmaceutical composition of the invention for the preparation of a pharmaceutical composition for the treatment of a metabolic disorder. Further, the present invention relates to a method for preparing a pharmaceutical composition and a compound of the present invention. [Prior Art] In the literature, a compound having an inhibitory effect on the sodium-dependent glucose co-transporter SGLT2 has been proposed for the treatment of diseases, particularly diabetes.

經葡萄糖哌喃基氧基及葡萄糖哌喃基取代之芳族基團及其製備及其作為SGLT2抑制劑之可能活性自以下公開之國際申請案中已知：WO 98/31697、WO 01/27128、WO 02/083066、WO 03/099836、WO 2004/063209、WO 2004/080990、WO 2004/0131 18、WO 2004/052902 > WO 2004/052903、WO 2005/092877、WO 06/010557、WO 06/018150 、WO 06/037537、WO 06/089872 、WO 124938.doc 200829258 2006/064033、WO 2007/093610 β * m 士 ± * 及吴國申請案US 2003/ 0114390。【發明内容】本發明之目標本發明之目標為發現新穎的㈣喃糖基取代之苯甲赌衍生物，尤#為對於納依賴性葡萄糖共轉運體sglt(尤其 SGLT2)具有活性之彼㈣生物。本發明之另—目標為發現在活體外及/或活體内對納依賴性葡萄糖共轉運體$町2具有良好至極為良好之抑制作用及/或良好至極為良好之藥理學及/或藥物動力學及/或物理化學特性的經㈣糖基取代之苯衍生物。本發明之另—目標為提供新穎醫藥組合物，其適於預防及/或治療代謝病症，尤其糖尿病。本發明亦著手提供用於製備本發明之化合物之方法。對於熟練技術者而言，本發明之其他目標將因上述及下述論述變得顯而易見。本發明之目的在弟：恶樣中’本發明係關於通式1之經葡萄糖哌喃基取代之苄基笨甲腈衍生物：Aromatic groups substituted with glucose piperacyloxy and glucose piperyl groups and their preparation and their possible activity as inhibitors of SGLT2 are known from the international applications disclosed below: WO 98/31697, WO 01/27128 WO 02/083066, WO 03/099836, WO 2004/063209, WO 2004/080990, WO 2004/0131 18, WO 2004/052902 > WO 2004/052903, WO 2005/092877, WO 06/010557, WO 06 /018150, WO 06/037537, WO 06/089872, WO 124938.doc 200829258 2006/064033, WO 2007/093610 β * m ± ± * and Wu Guo application US 2003 / 0114390. OBJECTS OF THE INVENTION The object of the present invention is to find novel (tetra)-n-glycosyl-substituted benzoquinone derivatives, especially for the nano-dependent glucose co-transporter sglt (especially SGLT2). . Another object of the present invention is to find a good to very good inhibitory effect on the nano-dependent glucose co-transporter $2 in vitro and/or in vivo and/or good to very good pharmacology and/or pharmacokinetics. (4) Glycosyl-substituted benzene derivatives of learning and/or physicochemical properties. Another object of the invention is to provide novel pharmaceutical compositions suitable for the prevention and/or treatment of metabolic disorders, especially diabetes. The invention also provides methods for preparing the compounds of the invention. Other objects of the present invention will become apparent to those skilled in the art from the foregoing description. OBJECTS OF THE INVENTION In the present invention, the present invention relates to a glucopicanyl substituted benzyl bumene derivative of the formula 1:

124938.doc 200829258 其中： R2 ί ' 表示氟、氯、溴、碘、Ci-6烷基、C2-6烯基、c2.6 炔基、Cw環烷基、c3_7環烷基-Cw烷基、羥基、 Cw烷氧基、c3_7環烷基氧基、c5_7環烯基氧基、 C 1 烧基硫基、胺基、确基或氰基，同時以上提及之烷基-、烯基-、炔基-、環烷基_及環烯基-殘基可經氟單或多取代及/或經相同或不同取代基L2單或雙取代，且同時在以上提及之C5_6環烷基及C5_6環烯基環中， 1個或2個亞甲基可彼此獨立地經〇、s、CO、SO 或so2置換，且 R3 Ο 表示氫、氟、氯、溴、碘、Cw烷基、C2_6炔基、 C2-6烯基、（：3-7環烷基、c3_7環烷基-Cw烷基、c5_7 環烯基、Cw環烯基-Ci-3烷基、芳基、雜芳基、 C!_4烷基羰基、芳基羰基、雜芳基羰基、胺基羰基、C】·4烷基胺基羰基、二（Cl_3烷基）胺基羰基、吼洛变-1-基幾基、派17定-1-基幾基、嗎琳·4_基獄基、哌嗪-1-基羰基、‘（Cw烷基）哌嗪-1-基羰基、羥基羰基、Ci.4烧氧基羰基、Ci_4烷基胺基、二（Cl·3烧基）胺基、吼略σ定-1-基、略唆_1_基、嗎啉-4-基、哌嗪-1-基、4-(C〗_4烷基）哌嗪-1-基、Ci.4 烷基羰基胺基、芳基羰基胺基、雜芳基羰基胺基、C!·4烧基磺酿基胺基、芳基磺酸基胺基、CN6 烧氧基、C3_7環烧基氧基、C5-7環烯基氧基、芳基 124938.doc 200829258 f 氧基、雜芳基氧基、CU4烷基疏基、C!-4烷基亞磺 ^基、Ci_4^基續酿基、C3.7環院基硫基、C3-7環烷基亞磺醯基、C3.7環烷基磺醯基、C5-7環烯基硫基、C5_7環稀基亞磺酸基、C5_7環烯基績醯基、芳基硫基、芳基亞磺醯基、芳基磺醯基、雜芳基硫基、雜方基亞續酸基、雜芳基石黃酿基、胺基、經基、氰基及硝基，同時以上提及之烷基-、烯基-、炔基-、環烷基_及環烯基-殘基可經氟單或多取代及/或經相同或不同取代基L2單或雙取代，且同時在以上提及之C5·6環烷基及c5_6環烯基環中， 1個或2個亞曱基可彼此獨立地經〇、s、c〇、s〇或so2置換，且同時在以上提及之N-雜環烷基環中，1個亞甲基可經C0或so2置換，且 R4、 G R彼此獨立地表示氫、氟、氯、漠、破、氛基、硝基、Cu烷基、Cl_3烷氧基，或經丨至）個氟原子取代之甲基或甲氧基， Ll 彼此獨立地選自氣、氯、溴、硬、經基、氰基、 f1-3烷基、二氟甲基、三氟甲基、Cl-3烷氧基、二氟甲氧基 '三氣甲氧基、胺基、k烧基-胺基及二（Ci-3烧基）-胺基；且 L2 彼此獨立地選自氟、氯、經基、經基-Cl-4烧基、 C!-4烧氧基、二氟甲氧基、Cm烧氧基/Μ烧基、 124938.doc 200829258 氰基、經基戴基、（Cw烧基）氧基叛基、胺基羧基、C1-4烷基、三氟甲基、胺基、Cw烷基·羰基胺基、CK3烷基-胺基及二（Cw烷基）-胺基；且 R6、R7a、 R7b、R7e彼此獨立地具有選自氫、（Ci i8烷基）羰基、（Ci i8 燒基）氧基羰基、芳基羰基及芳基烷基）-羰基之含義，同時芳基可經相同或不同基團L1彼此獨立地單或雙取代；同時以上基團之定義中提及之芳基係意謂可如定義取代之苯基或萘基；且同柃除非另外說明，否則以上提及之烷基可為直鏈或支鏈烷基，其互變異構體、立體異構體、其混合物及其鹽。124938.doc 200829258 wherein: R2 ί ' represents fluoro, chloro, bromo, iodo, Ci-6 alkyl, C2-6 alkenyl, c2.6 alkynyl, Cw cycloalkyl, c3-7 cycloalkyl-Cw alkyl, a hydroxy group, a Cw alkoxy group, a c3-7 cycloalkyloxy group, a c5-7 cycloalkenyloxy group, a C 1 alkylthio group, an amine group, an exact group or a cyano group, and the above-mentioned alkyl-, alkenyl-, The alkynyl-, cycloalkyl- and cycloalkenyl-residues may be mono- or polysubstituted by fluorine and/or mono- or di-substituted with the same or different substituents L2, and at the same time the C5_6 cycloalkyl and C5_6 mentioned above In the cycloalkenyl ring, 1 or 2 methylene groups may be independently substituted with hydrazine, s, CO, SO or so2, and R3 Ο represents hydrogen, fluorine, chlorine, bromine, iodine, Cw alkyl, C2_6 alkyne , C 2-6 alkenyl, (: 3-7 cycloalkyl, c 3-7 cycloalkyl-Cw alkyl, c 5-7 cycloalkenyl, C w cycloalkenyl-Ci-3 alkyl, aryl, heteroaryl, C !_4 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, C 4 alkylaminocarbonyl, bis(Cl 3 alkyl)aminocarbonyl, indolyl-1-yl, and 17-1-indolyl, morphine, 4, phenyl group, piperazin-1-ylcarbonyl, '(Cw alkyl) Pyrazin-1-ylcarbonyl, hydroxycarbonyl, Ci.4 alkoxycarbonyl, Ci_4 alkylamino, bis(Cl·3 alkyl)amine, σσσ-1-yl, slightly 唆_1_yl , morpholin-4-yl, piperazin-1-yl, 4-(C)-4-alkylpiperazin-1-yl, Ci.4 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonyl Amino, C!·4 alkylsulfonylamino, arylsulfonylamino, CN6 alkoxy, C3_7 cycloalkyloxy, C5-7 cycloalkenyloxy, aryl 124938.doc 200829258 f oxy, heteroaryloxy, CU4 alkyl thiol, C!-4 alkyl sulfinyl, Ci_4 yl aryl, C 3.7 ring thiol, C 3-7 cycloalkyl Sulfonyl, C3.7 cycloalkylsulfonyl, C5-7 cycloalkenylthio, C5-7 cyclopentylenesulfinyl, C5-7 cycloalkenyl, arylthio, arylsulfin Alkyl, arylsulfonyl, heteroarylthio, heteroarylsulfonyl, heteroaryl fluorenyl, amine, thiol, cyano and nitro, and the alkyl- Alkenyl-, alkynyl-, cycloalkyl- and cycloalkenyl-residues may be mono- or polysubstituted by fluorine and/or mono- or di-substituted with the same or different substituents L2, and simultaneously In the C5·6 cycloalkyl and c5_6 cycloalkenyl rings mentioned, 1 or 2 fluorenylene groups may be independently substituted with hydrazine, s, c〇, s〇 or so2, and at the same time mentioned above In the N-heterocycloalkyl ring, one methylene group may be substituted by C0 or so2, and R4 and GR independently represent hydrogen, fluorine, chlorine, desert, broken, aryl, nitro, Cu alkyl, Cl_3. An alkoxy group, or a methyl or methoxy group substituted by a fluorine atom, wherein L1 is independently selected from the group consisting of gas, chlorine, bromine, hard, thiol, cyano, f1-3 alkyl, difluoromethyl a group, a trifluoromethyl group, a Cl-3 alkoxy group, a difluoromethoxy group, a tri-methoxy group, an amine group, a k-alkyl group, an amine group, and a bis(Ci-3 alkyl)-amine group; Independently from each other selected from the group consisting of fluorine, chlorine, mercapto, trans-co-4 alkyl, C!-4 alkoxy, difluoromethoxy, Cm alkoxy/anthracenyl, 124938.doc 200829258 cyano , by base group, (Cw alkyl)oxyl group, aminocarboxyl group, C1-4 alkyl group, trifluoromethyl group, amine group, Cw alkylcarbonylamino group, CK3 alkyl-amino group and (Cw alkyl)-amino group; and R6, R7a, R7b, R7e independently of each other have a selected from hydrogen, (Ci i8 a carbonyl group, a (Ci i8 alkyl)oxycarbonyl group, an arylcarbonyl group, and an arylalkyl)-carbonyl group, wherein the aryl group may be mono- or disubstituted independently of each other via the same or different groups L1; The aryl group referred to in the definition of a group means a phenyl or naphthyl group which may be substituted as defined; and the same as the above, the alkyl group mentioned above may be a linear or branched alkyl group, which is mutually mutated. Constructs, stereoisomers, mixtures thereof and salts thereof.

本發明亦係關於本發明化合物與無機酸或有機酸之生理學上可接受之鹽。本發明亦係關於醫藥組合物，其含有至The invention also relates to physiologically acceptable salts of the compounds of the invention with inorganic or organic acids. The invention also relates to pharmaceutical compositions containing to

>'一種本發明之視情況以及一或多種惰性載劑及/或稀釋劑。其含有至少受之鹽，親 124938.doc -10- 200829258 本ι明亦係關於至少一種本發明之化合物或其生理學上可接文之鹽中之—者的用途，其係用於製備適於治療或預防可又抑制鈉依賴性葡萄糖共轉運體(尤其sglt2)影響之疾病或病狀之醫藥組合物。 u本毛m系關於至少—種本發明之化合物或其生理學上可接又之鹽中之—者的用途，其係用於製備適於治療代謝病症之醫藥組合物。> 'A case of the invention and one or more inert carriers and/or diluents. It contains at least the salt, pro 124938.doc -10- 200829258 ι is also used in at least one of the compounds of the present invention or a physiologically acceptable salt thereof, which is suitable for preparation A pharmaceutical composition for treating or preventing a disease or condition which, in turn, inhibits the effects of a sodium-dependent glucose co-transporter, particularly sglt2. U is a use of at least one of the compounds of the present invention or a physiologically acceptable salt thereof for the preparation of a pharmaceutical composition suitable for the treatment of a metabolic disorder.

在另恶樣中，本發明係關於至少—種本發明之化合物，/、生里予上可接x之鹽中之一者的用途，其係用於製備用乂預防騰腺β'細胞退化及/或用於改良及/或恢復騰腺卜細胞功能性之醫藥組合物。在另1樣中，本發明係關於至少一種本發明之化合物或其生理學上可拉為+ 、予上J接又之鹽中之一者的用途，其係用於製備用以預防、減緩、延遲或治療有此需要之患者中由肝臟脂肪異常積聚引起之疾病或病狀的醫藥組合物。本:明亦係關於至少-種本發明之化合物或其生理學上In another example, the present invention relates to the use of at least one of the compounds of the present invention, and one of the salts of x, which is used for the preparation of a sputum for preventing β-cell degeneration. And/or a pharmaceutical composition for improving and/or restoring the function of adenine cells. In another example, the invention relates to the use of at least one compound of the invention or one of its physiologically cleavable +, and a salt of the same, which is used for preparation for prevention, mitigation A pharmaceutical composition that delays or treats a disease or condition caused by abnormal accumulation of liver fat in a patient in need thereof. Ben: Ming is also related to at least one of the compounds of the present invention or physiologically

""口JT _ I 、用途’其係用於製備用於抑制鈉依賴性葡萄糖共轉運體SGLT(尤其SGLT2)之醫藥組合物。《月進纟係關於製備本發明之醫藥組合物之方法， /、特徵在於將本發明之化合物或其生理學上可接受之鹽中之一者由非化學方法從决併入一或多種惰性載劑及/或稀釋劑 T 0 本發明亦係關於特徵在於：製備本發明之通式I化合物之方法，其 124938.doc 200829258 a)為製備上文及下文中所定義之通式丨化合物，使通式II化合物："" mouth JT_I, use' is used to prepare a pharmaceutical composition for inhibiting the sodium-dependent glucose co-transporter SGLT (especially SGLT2). The method for preparing a pharmaceutical composition of the present invention, characterized in that one of the compounds of the present invention or a physiologically acceptable salt thereof is non-chemically incorporated into one or more inert Carrier and/or Diluent T 0 The present invention is also directed to a process for the preparation of a compound of Formula I of the present invention, 124938.doc 200829258 a) for the preparation of a hydrazine compound of the formula defined above and below, To make a compound of formula II:

其中：among them:

Rl 表示氰基、氯或溴； R 表示Η、Ci_4燒基、（Ci-18烧基）幾基、（Cl-18烧基）氧基羰基、芳基羰基及芳基兴C1.3烷基）-羰基’其中烷基或芳基可經鹵素單或多取代； R8a、R8b、 R8c、R8d彼此獨立地具有上文及下文關於基團R6、 R & ' R7b、R7e所給出含義中之一者，或表示苄基或烯丙基或RaRbReSi基團或縮酮或縮醛基團，尤其表不亞烷基或芳基亞烷基縮酮或縮醛基團，同時在各情況下兩個相鄰基團RSa、 8 b R R可形成環狀妙烧基縮酮、縮_ 或縮醛基團或L2-二（Cw烷氧基H，2_二（Ci3 说基）-伸乙基橋，同時以上提及之伸乙基橋與哌喃糖環之兩個氧原子及兩個相關碳原子二起形成經取代之二嚼烷環’尤其為2,3_二甲基烷氧基二噁烷環，且同時烷基、芳基及/或节基可㈣素或CM烷氡: 124938.doc 1Λ 200829258 單或多取代’ i同時苄基亦可經二(Cl ;烷基) 胺基取代；且 f Rb、V彼此獨立地表叫_4院基、芳基或芳基&燒基其中芳基或燒基可經鹵素單或多取代· 同時以上基團之定義中提及之芳基係意謂苯基或蔡基，較佳為苯基； 1 且其中基團R2至R6、R7a、R7b 定義；Rl represents cyano, chloro or bromo; R represents hydrazine, Ci_4 alkyl, (Ci-18 alkyl), (Cl-18 alkyl)oxycarbonyl, arylcarbonyl and aryl C1.3 alkyl a carbonyl group wherein the alkyl or aryl group may be mono- or polysubstituted by halogen; R8a, R8b, R8c, R8d independently of one another have the meanings given above and below with respect to the groups R6, R & 'R7b, R7e Or one of a benzyl or allyl or RaRbReSi group or a ketal or acetal group, especially an alkylene or arylalkylene ketal or acetal group, in each case Two adjacent groups RSa, 8 b RR may form a cyclic ketal, a condensed or acetal group or a L2-di (Cw alkoxy H, 2_di(Ci3)-) a bridge, at the same time, the above-mentioned extension of the ethyl bridge and the two oxygen atoms of the pipetose ring and two related carbon atoms form a substituted dicetane ring, especially 2,3-dimethylalkoxy a dioxagen ring, and at the same time an alkyl group, an aryl group and/or a cyclyl group (tetra) or a CM alkane: 124938.doc 1Λ 200829258 Single or multiple substituted 'i simultaneous benzyl group may also be passed through two (Cl; alkyl) Amine substitution; and f Rb, V Independently referred to as _4, aryl or aryl &aryl; wherein the aryl or alkyl group may be mono- or polysubstituted by halogen; and the aryl group mentioned in the definition of the above group means phenyl or ca. a group, preferably a phenyl group; 1 and wherein the groups R2 to R6, R7a, R7b are defined;

R7e係如上文及下文中所在路易斯酸（Lewis acid)或布忍斯特酸（以抓“以扣^)存在下與還原劑反應，同時所存在之任何保護基同時或相繼裂解；若在式π化合物w表示CUBr，則在隨後之轉化中，使R1之個別鹵素原子經氰基置換；或 b)為製備RWb及R7C表示氫之通式他合物，將通式III化合物水解：R7e is reacted with a reducing agent in the presence of Lewis acid or Brucenic acid as described above and below, while any protecting groups present are simultaneously or sequentially cleaved; The compound w represents CUBr, and in the subsequent conversion, the individual halogen atoms of R1 are replaced by a cyano group; or b) is a compound of the formula RWb and R7C represents hydrogen, and the compound of the formula III is hydrolyzed:

、右1要，則由醯化作用將因此獲得之汉6表示氫原子之通式1化合物轉化為相應通式I之醯基化合物，及/或要，則使上述反應中所用之任何保護基裂解及/或 124938.doc -13- 200829258 若需要，則將因此獲得之通式〗化合物解析為其立體異構體及/或若需要，則將因此獲得之通式j化合物轉化為其鹽，尤其為醫藥用途轉化為其生理學上可接受之鹽。本發明進一步係關於製備通式II化合物之方法：And the right one is, the compound of the formula 1 in which the hydrogen atom 6 represents a hydrogen atom is converted into the mercapto compound of the corresponding formula I by deuteration, and/or any protective group used in the above reaction is used. Pyrolysis and/or 124938.doc -13- 200829258 If desired, the compound of the formula thus obtained is resolved to its stereoisomer and/or, if desired, the compound of formula j thus obtained is converted to its salt, It is especially converted into a physiologically acceptable salt for medical use. The invention further relates to a process for the preparation of a compound of formula II:

R1 R，表示氰基、氯或溴； R8a、R8b、表示H、Cl.4烷基、（Cl_18烷基）羰基、（^，烷基）氧基羰基、芳基羰基及芳基-(Ci3烷基）_羰基’其中烷基或芳基可經鹵素單或多取代； -14- 1 ^ 彼此獨立地具有關於基團R6、R7a、R7b、r7c 所給出含義中一者，或表示苄基或烯丙基或 • RRbResi基團或縮酮或縮醛基團，同時在各情況下兩個相鄰基團R8a、R8b、r8c、R8d可形成 %狀矽烷基縮酮、縮_或縮醛基團或可與哌喃糖環之兩個氧原子形成經取代之2,3_氧基二噁烷環，尤其為2,3-二甲基_2,3_:(Cl_3烷氧基二噁烷環，且同時烷基、芳基及/或苄基可經鹵素或Ci-3烷氧基單或多取代，且同時 124938.doc 200829258 节基亦可經二（Cw烷基）胺基取代；且R1 R, represents cyano, chloro or bromo; R8a, R8b, represents H, Cl.4 alkyl, (Cl_18 alkyl)carbonyl, (^,alkyl)oxycarbonyl, arylcarbonyl and aryl-(Ci3 Alkyl)-carbonyl" wherein the alkyl or aryl group may be mono- or polysubstituted by halogen; -14- 1 ^ independently of one another has one of the meanings given for the group R6, R7a, R7b, r7c, or benzyl Or allyl or • RRbResi group or ketal or acetal group, in each case two adjacent groups R8a, R8b, r8c, R8d can form a % decyl ketal, shrinkage or shrinkage The aldehyde group may form a substituted 2,3-oxydioxane ring with two oxygen atoms of the pipetamose ring, especially 2,3-dimethyl-2,3_:(Cl_3 alkoxy An oxane ring, and at the same time an alkyl group, an aryl group and/or a benzyl group may be mono- or polysubstituted by halogen or a Ci-3 alkoxy group, and at the same time 124938.doc 200829258 may also be subjected to a bis(Cw alkyl)amino group. Replace

Ra、Rb、Re彼此獨立地表*Cl_4烷基、芳基或芳基_Cm烷基’同時烷基或芳基可經函素單或多取代；同時以上基團之定義中提及之芳基係意謂苯基或萘基，較佳為苯基；且R2至R6、R7、Rn、係如上文及下文所定義，其中將可藉由鹵素-金屬交換或在通式IV之鹵素_苄基苯化合物之碳-_鍵中***金屬而獲得且視情況隨後進行金屬父換的有機金屬化合物（V):Ra, Rb, Re independently of each other, *Cl_4 alkyl, aryl or aryl-Cm alkyl', while the alkyl or aryl group may be mono- or polysubstituted by a functional group; and the aryl group mentioned in the definition of the above group It means phenyl or naphthyl, preferably phenyl; and R2 to R6, R7, Rn, as defined above and below, which may be exchanged by halogen-metal or halogen-benzyl of formula IV The organometallic compound (V) obtained by inserting a metal into the carbon-_ bond of the benzene compound and optionally subjecting the metal parent to change:

其中Hal表示C1、以及1且R1表示CN、C1或Br，且…至！^ : 及下文所疋義’添加至通式VI之葡糖酸内g旨中： OR8dWhere Hal represents C1 and 1 and R1 represents CN, C1 or Br, and ... to! ^ : and hereinafter referred to as 'added to the gluconic acid of formula VI. g: OR8d

且And

VI R8d係如上文及下文所定義，VI R8d is as defined above and below,

Ik後在酸（諸如甲烷磺酸、硫酸、鹽酸、乙酸或氯化銨）存在下使所得加合物與水或醇r，-〇H(同時R，表示視情況經取代之C, # #、e ^ 14燒基）反應，且視情況使在與水（其中R，表示 124938.doc -15- 200829258 Η)之反應中所獲得之產物在隨後之反應中在酸存在下以醇轉化以產生烷氧基衍生物，或以醯化劑（諸如相應酸氯化物或酸酐）轉化為式„之產物，其中R，表示（Cii8烷基）羰基、烷基）氧基羰基、芳基羰基或芳基_(Ci 3烷基）_羰基，其可如所指定經取代。所列出之中間產物，尤其為彼等式][V、式„及式m之化合物’亦為本發明之標的。【實施方式】除非另外說明，否則基團、殘基及取代基，尤其R2至 R、Ll、L2、R6、R7a、R7b、R7。、R8a、R8b、r8c、R8d，係如上文及下文所定義。若殘基、取代基或基團在化合物中出現數次，例如L i及 L2 ’則其可能具有相同或不同之含義。本發明化合物之個別基團及取代基之一些較佳含義將在下文給出。本發明之較佳化合物可由式I· 1至L4描述：After Ik, the resulting adduct is combined with water or alcohol r, -〇H in the presence of an acid such as methanesulfonic acid, sulfuric acid, hydrochloric acid, acetic acid or ammonium chloride (while R, indicating C, as appropriate) , e ^ 14 alkyl) reaction, and optionally the product obtained in the reaction with water (wherein R, representing 124938.doc -15-200829258 Η) is converted with alcohol in the subsequent reaction in the presence of an acid. Producing an alkoxy derivative, or converting it to a product of the formula, such as R, for a (Cii8 alkyl)carbonyl, alkyl)oxycarbonyl, arylcarbonyl or Aryl-(Ci 3 alkyl)-carbonyl, which may be substituted as specified. The intermediates listed, especially those of the formula [V, formula and formula m] are also the subject of the invention. . [Embodiment] Unless otherwise stated, a group, a residue and a substituent, in particular, R2 to R, L1, L2, R6, R7a, R7b, R7. , R8a, R8b, r8c, R8d, as defined above and below. If a residue, substituent or group appears several times in a compound, such as L i and L 2 ', it may have the same or different meanings. Some of the preferred meanings of the individual groups and substituents of the compounds of the invention are given below. Preferred compounds of the invention can be described by Formulas I.1 through L4:

124938.doc -16- 200829258 1.2 1.3124938.doc -16- 200829258 1.2 1.3

NN

1.4 尤其較佳為如式i.i中所示於與苄基相鄰且與葡萄糖部分相對之中心芳族基上具有氰基之化合物。基團R較佳表示氟、氯、溴、經基、氰基、c 1 4烧基、烷基氧基、CP環烷基、CP環烷基氧基或烷基硫基，同時在C5_6環烷基環中，亞甲基可經〇置換，且其中任何烧基或環烧基環可經單或多氟化及/或經相同或不同之取代基L2單或雙取代。 R2之尤其較佳含義為氣、溴、甲基、乙基、氰基、羥基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基、環戊基、環丙基氧基、環丁基氧基、環戊基氧基、四氫呋喃-3_ 基氧基、四氫哌喃基氧基、甲基硫基、乙基硫基；尤其為 124938.doc -17- 200829258 甲基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙基、環丁基氧基、（（3 S)-四氫呋喃-3-基）氧基、（（3R)-四氫呋喃-3-基）氧基、甲基硫基及氰基。R2最佳表示甲基、羥基或甲氧基。基團R3之較佳含義為氯、漠、蛾、Ci-4烧基、C3-7環炫基、羥基、Cw烷基氧基、C3-7環烷基氧基、Cw烷基硫基、C3_7環烷基硫基，同時在c5-6環烷基環中，亞甲基可經〇置換’且其中任何烷基或環烷基環可經單或多氟化及/或經相同或不同之取代基L2單或雙取代。基團R3之更佳含義為氯、溴、曱基、乙基、丙基、異丙基、環丙基、丁基、第二丁基、異丁基、第三丁基、二氟甲基、二氟甲基、2-經基-乙基、經基甲基、3-經基-丙基、2-羥基-2-曱基-丙-；[•基、％羥基_3_曱基-丁-1-基、1-經基-1-甲基-乙基、2_甲氧基-乙基、2_乙氧基-乙基、羥基、甲氧基、乙氧基、異丙氧基、二氟甲氧基、三氟甲氧基、環丁氧基、環戊氧基、環己基氧基、四氫呋喃-3- 基氧基、（及>四氫呋喃-3-基氧基、四氫哌喃-4-基氧基、甲基硫基及乙基硫基。 R甚至更佳表示甲基、乙基、正丙基、異丙基、環丙基、甲氧基、乙氧基、異丙氧基、甲基硫基或乙基硫基，尤其為乙基或環丙基。基團R之較佳含義為氫及氟，尤其為氫。基團R之較佳含義為氫及氟，尤其為氫。基團L1之較佳含義彼此獨立地選自氣、氣、漠、氛基、 124938.doc -18 · 200829258 、土 Cl-3燒基、二氟甲基、三氟甲基、Ci 垸氧基、二氟曱氧基、二氟甲氧基及二（CN3烷基）-胺基。基團L1之甚至更佳含義選自氟、氯、羥基、三氟甲基、乙基、甲氧基、乙氧基及二甲基胺基，尤其為甲基、乙基、甲氧基、乙氧基及二甲基胺基。基團L2之較佳含義彼此獨立地選自氟、羥基、羥基_Cl_4 …土 Cl_4烷氧基、Ci·4烷氧基-Cw烷基、c1-4烷基、三氟甲基、C!_4烷基_羰基胺基、羥基羰基及烷氧基羰基。基團L2之甚至更佳含義選自氟、羥基、羥基烷基、 C!-4烷氧基、Cl·4烷氧基/μ烷基、cw烷基、羥基羰基及 C!-4烷氧基羰基；尤其為羥基、羥基甲基、甲氧基甲基、甲氧基、甲基、羥基羰基、甲氧基羰基及乙氧基羰基。根據本發明基團R6較佳表示氫、（Ci 8烷基）氧基羰基、 Cw烷基羰基或苯甲醯基，尤其為氫或（Ci0烷基）氧基羰基或Cl·6烷基羰基，尤其較佳為氫、甲基羰基、甲氧基羰基或乙氧基羰基，尤其最佳為氫。取代基R7a、R7b、Rk較佳彼此獨立地表示氫、烷基）氧基羰基、（CN18烷基）羰基或苯甲醯基，尤其為氫、 (C!-6烷基）氧基羰基或（Cl_8烷基）羰基，尤其較佳為氫、甲氧基羰基、乙氧基羰基、甲基羰基或乙基羰基。、R7b 及R7e尤其最佳表示氫。根據本發明R6、R7、及具有不為氫之含義（例如 C!-8烷基羰基）之式I化合物較佳適合作為合成R6、Rh、R7b 及R7c表示氫之式I化合物之中間產物。 124938.doc •19- 200829258 尤其較佳之通式1化合物係選自式Lla至L1C，尤其選自 • la及 I.lb :1.4 Particularly preferred is a compound having a cyano group on the central aromatic group adjacent to the benzyl group and opposite to the glucose moiety as shown in the formula i.i. The group R preferably represents fluorine, chlorine, bromine, thiol, cyano, c 1 4 alkyl, alkyloxy, CP cycloalkyl, CP cycloalkyloxy or alkylthio, while at the C5-6 ring In the alkyl ring, the methylene group may be substituted with hydrazine, and any of the alkyl or cycloalkyl rings may be mono- or poly-fluorinated and/or mono- or di-substituted with the same or different substituents L2. Particularly preferred meanings of R2 are gas, bromine, methyl, ethyl, cyano, hydroxy, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl. Oxyl, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydropyranyloxy, methylthio, ethylthio; especially 124938.doc -17- 200829258 Base, ethyl, hydroxy, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyloxy, ((3S)-tetrahydrofuran-3-yl)oxy, ((3R)- Tetrahydrofuran-3-yl)oxy, methylthio and cyano. R2 preferably represents a methyl group, a hydroxyl group or a methoxy group. Preferred meanings of the group R3 are chlorine, moth, moth, Ci-4 alkyl, C3-7 cyclod, hydroxy, Cw alkyloxy, C3-7 cycloalkyloxy, Cw alkylthio, C3_7 cycloalkylthio, while in the c5-6 cycloalkyl ring, the methylene group may be substituted by hydrazine and wherein any alkyl or cycloalkyl ring may be mono- or polyfluorinated and/or identical or different The substituent L2 is mono- or di-substituted. More preferred meaning of the group R3 is chlorine, bromine, decyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, t-butyl, isobutyl, tert-butyl, difluoromethyl , difluoromethyl, 2-carbyl-ethyl, transmethyl, 3-hydroxy-propyl, 2-hydroxy-2-indenyl-propyl-; [•, % hydroxy_3_ fluorenyl -but-1-yl, 1-carbyl-1-methyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, methoxy, ethoxy, isopropyl Oxyl, difluoromethoxy, trifluoromethoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuran-3-yloxy, (and > tetrahydrofuran-3-yloxy, Tetrahydropyran-4-yloxy, methylthio and ethylthio. R even more preferably represents methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy Base, isopropoxy, methylthio or ethylthio, especially ethyl or cyclopropyl. The preferred meaning of the radical R is hydrogen and fluorine, especially hydrogen. The preferred meaning of the radical R is Hydrogen and fluorine, especially hydrogen. The preferred meanings of the group L1 are independently selected from the group consisting of gas, gas, desert, and atmosphere. 124938.doc -18 · 200829258 Soil Cl-3 alkyl, difluoromethyl, trifluoromethyl, Ci decyloxy, difluoromethoxy, difluoromethoxy and bis(CN3 alkyl)-amine groups. Even more of the group L1 Preferred meanings are selected from the group consisting of fluorine, chlorine, hydroxyl, trifluoromethyl, ethyl, methoxy, ethoxy and dimethylamino, especially methyl, ethyl, methoxy, ethoxy and dimethyl Preferred meanings of the group L2 are independently selected from the group consisting of fluorine, hydroxyl, hydroxy_Cl_4 ... soil Cl_4 alkoxy, Ci. 4 alkoxy-Cw alkyl, c1-4 alkyl, trifluoromethyl Further, C! 4 alkyl-carbonylamino, hydroxycarbonyl and alkoxycarbonyl. Even more preferred meaning of the group L2 is selected from the group consisting of fluorine, hydroxyl, hydroxyalkyl, C!-4 alkoxy, Cl.4 alkane. Oxyl/μalkyl, cw alkyl, hydroxycarbonyl and C!-4 alkoxycarbonyl; especially hydroxy, hydroxymethyl, methoxymethyl, methoxy, methyl, hydroxycarbonyl, methoxy Carbonyl and ethoxycarbonyl. The group R6 according to the invention preferably represents hydrogen, (Ci 8 alkyl)oxycarbonyl, Cw alkylcarbonyl or benzhydryl, especially hydrogen or (Ci0 alkyl)oxycarbonyl Or a Cl 6 alkylcarbonyl group, particularly preferably Hydrogen, methylcarbonyl, methoxycarbonyl or ethoxycarbonyl, especially preferably hydrogen. The substituents R7a, R7b, Rk preferably independently of each other represent hydrogen, alkyl)oxycarbonyl, (CN18 alkyl)carbonyl Or benzhydryl, especially hydrogen, (C!-6 alkyl)oxycarbonyl or (Cl-8 alkyl)carbonyl, especially preferably hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or Alkylcarbonyl. R7b and R7e are particularly preferably hydrogen. The compounds of the formula I according to the invention, R6, R7, and having the meaning of not hydrogen (for example C?-8 alkylcarbonyl) are preferably suitable as intermediates for the synthesis of compounds of the formula I in which R6, Rh, R7b and R7c represent hydrogen. 124938.doc • 19- 200829258 Particularly preferred compounds of formula 1 are selected from the formulae Lla to L1C, especially selected from • la and I. lb:

〇2〇2

R3 - R3 - R3 之一者，尤其具有所給出於中One of R3 - R3 - R3, especially with the given

印夺曰疋為較佳之含義中之一者；且尤其：表示I氯、、;臭、氰基、Ci_4烧基、經基、c“ 焼4基氧基、環烷基、C3-7環烷基氧基或Ci.3 烧基硫基’同時在C5 6環烷基環中，亞甲基可經0置換’且其中任何烷基或環烷基環可經單或多敗化及/或經相同或不同之取代基L2單或雙取代·’ R2甚至更隹表示氣、溴、曱基、乙基、氣基、羥基、甲氧基、乙氧基、異丙氧 124938.doc -20- 200829258 基、環丙基、環丁基、環戊基、環丙基氧基、環丁基氧基、環戊基氧基、四氫呋喃-3-基氧基、四氫哌喃基氧基、甲基硫基、乙基硫基； R2最佳表示曱基、乙基、羥基、甲氧基、乙氧基、異丙氧基、環丙基或環丁基氧基；且表示氯、溴、碘、C!_4烷基、C3_7環烷基、羥基、Cm烷基氧基、c3_7環烷基氧基、Cw烷基硫基、CP環烷基硫基，同時在c5_6環烷基環中’亞甲基可經0置換，且其中任何院基或環烷基環可經單或多氟化及/或經相同或不同之取代基L2單或雙取代；R3甚至更佳表示氯、溴、甲基、乙基、丙基、異丙基、環丙基、丁基、第二丁基、異丁基、第三丁基、二氟甲基、三氟曱基、2-羥基-乙基、羥基甲基、3·羥基-丙基、2-羥基-2-甲基-丙-1-基、3-羥基-3-甲基· 丁-1-基、1-羥基-1_甲基_乙基、入甲氧基_乙基、2-乙氧基-乙基、經基、甲氧基、乙氧基、異丙氧基、二氟甲氧基、三氟甲氧基、環丁氧基 ^衣戍氧基、$衣己基氧基、（$) -四氮ϋ夫喃-3 _ 基氧基、四氫呋喃-3-基氧基、四氫哌喃-4-基氧基、甲基硫基及乙基硫基；R3最佳表示甲基、乙基、正丙基、異丙基、環丙基、甲氧基、乙氧基、異丙氧基、曱基硫基或乙基硫基；且 124938.doc -21 · 200829258 R 表示氫或氟，尤其表示氫；且 R 表示氫或氟，尤其表示氫；且 L2 彼此獨立地選自氟、羥基、羥基-Cw烷基、Cw 烧氧基、C!·4烷氧基-Cl4烷基、Cl_4烷基、三氟甲基、Cw烧基-羰基胺基、羥基羰基及Cl_4烷基氧基羰基；尤其表示羥基、羥基甲基、曱氧基曱基、甲氧基、甲基、羥基羰基、甲氧基羰基及乙氧基魏基；且印曰疋 is one of the preferred meanings; and in particular: represents I chloro,, odor, cyano, Ci_4 alkyl, thiol, c " 焼 4 yloxy, cycloalkyl, C3-7 ring An alkyloxy group or a Ci.3 alkylthio group 'in a C5 6 cycloalkyl ring, the methylene group may be substituted by 0' and any of the alkyl or cycloalkyl rings may be mono- or poly- and/or Or mono- or di-substituted by the same or different substituents L2 · 'R2 even more 隹 represents gas, bromine, mercapto, ethyl, gas, hydroxyl, methoxy, ethoxy, isopropoxy 124938.doc - 20- 200829258, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydropyranyloxy , methylthio, ethylthio; R2 preferably represents fluorenyl, ethyl, hydroxy, methoxy, ethoxy, isopropoxy, cyclopropyl or cyclobutyloxy; and represents chlorine, Bromine, iodine, C!_4 alkyl, C3_7 cycloalkyl, hydroxy, Cm alkyloxy, c3-7 cycloalkyloxy, Cw alkylthio, CP cycloalkylthio, simultaneously in the c5-6 cycloalkyl ring Medium 'methylene group can be replaced by 0, and any of them The pendant or cycloalkyl ring may be mono- or polyfluorinated and/or mono- or di-substituted with the same or different substituent L2; R3 even more preferably represents chloro, bromo, methyl, ethyl, propyl, isopropyl Base, cyclopropyl, butyl, second butyl, isobutyl, tert-butyl, difluoromethyl, trifluoromethyl, 2-hydroxy-ethyl, hydroxymethyl, 3 hydroxy-propyl , 2-hydroxy-2-methyl-propan-1-yl, 3-hydroxy-3-methyl.butan-1-yl, 1-hydroxy-1-methyl-ethyl, methoxy-ethyl , 2-ethoxy-ethyl, mercapto, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclobutoxy, oxime, Hexyloxy, ($)-tetrazinoxa-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, methylthio and ethylthio; R3 Most preferably represents methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, decylthio or ethylthio; and 124938.doc -21 · 200829258 R represents hydrogen or fluorine, especially hydrogen; and R represents hydrogen or fluorine, especially hydrogen; and L2 is independently selected from fluorine, hydroxy , hydroxy-Cw alkyl, Cw alkoxy, C!·4 alkoxy-Cl4 alkyl, Cl_4 alkyl, trifluoromethyl, Cw alkyl-carbonylamino, hydroxycarbonyl and Cl-4 alkyloxycarbonyl Especially indicating a hydroxyl group, a hydroxymethyl group, a decyloxy group, a methoxy group, a methyl group, a hydroxycarbonyl group, a methoxycarbonyl group, and an ethoxy group;

R 表示氫、（C1·6烷基）氧基羰基、（Cw烷基）羰基或苯甲醯基，尤其表示氫、甲基羰基、甲氧基羰基或乙氧基羰基，尤其最佳表示氫；且 R7a、R7b、R7e彼此獨立地表示氫、（Ci 6烷基）氧基羰基、 (Cw烷基）羰基或苯甲醯基，尤其表示氫、甲氧基羰基、乙氧基羰基、甲基羰基或乙基羰基，尤其較佳表示氫；包括其互變異構體、立體異構體、混合物及其鹽。根據本發明之另_變化形式’較佳為在隨後之實驗部分中心疋之通式I化合物及其衍生物，#中根據本發明尺6具有=為氫之含義，尤其其巾R6表*乙醯基、乙氧基幾基或甲氧基幾基，包括其互變異構體、立體異構體及其混合物0 根據本發明之方法中，基團R2至R5較佳具有上文指定較佳之含義。此外R|較佳表示H、Ci 3院基或节基，尤其表不Η、乙基或甲基。基團R8a、R8b、心及…彼此獨立地較 124938.doc -22- 200829258 佳表示H、Ci_4烧基戴基或卡基’尤其表示Η、曱基幾基、乙基羰基或苄基。本發明亦係關於通式IV化合物：R represents hydrogen, (C1-6 alkyl)oxycarbonyl, (Cw alkyl)carbonyl or benzhydryl, especially hydrogen, methylcarbonyl, methoxycarbonyl or ethoxycarbonyl, especially preferably hydrogen And R7a, R7b, R7e independently of each other represent hydrogen, (Ci 6 alkyl)oxycarbonyl, (Cw alkyl)carbonyl or benzhydryl, especially hydrogen, methoxycarbonyl, ethoxycarbonyl, A A carbonyl group or an ethyl carbonyl group, particularly preferably a hydrogen; includes tautomers, stereoisomers, mixtures thereof and salts thereof. Further variants according to the invention are preferably compounds of the formula I and derivatives thereof in the subsequent experimental part, in which the ruler 6 according to the invention has the meaning of hydrogen, in particular its towel R6 table*B Indenyl, ethoxylated or methoxyl, including tautomers, stereoisomers and mixtures thereof. 0 In accordance with the process of the present invention, the groups R2 to R5 preferably have the above specified preferences. meaning. Further, R| preferably represents a H or Ci 3 or a radical, especially an ethyl, ethyl or methyl group. The groups R8a, R8b, nucleus and ... are independently of each other. 124938.doc -22-200829258 preferably denotes H, Ci_4 alkylidyl or kaki' especially denotes anthracene, fluorenyl, ethylcarbonyl or benzyl. The invention also relates to compounds of formula IV:

其中Hal表示氯、溴或碘，Ri表示氰基、氣或溴，尤其表示氰基，且基團R2至R5係如上文所定義，其在合成本發明之化合物中作為中間產物或起始物質。基團R2至R5尤其較佳具有隨式I.la給出之含義。本發明亦係關於通式Π化合物：Wherein Hal represents chlorine, bromine or iodine, Ri represents cyano, gas or bromine, especially cyano, and the radicals R2 to R5 are as defined above, as intermediates or starting materials in the synthesis of the compounds of the invention . The radicals R2 to R5 are especially preferably of the meaning given by the formula I.la. The invention is also related to the general formula:

尤其較佳具有隨式1.1 a a至I.lc給出之含義。、R8d及R1至R5係如上文及下文所定 k C】·3烷基或苄基，尤其表示H、乙、氯或漠’尤其表示氰基或溴；且 8(1彼此獨立地表示H、ci 4烷基羰其表不Η、甲基羰基、乙基羰基或如上文所定義。該等化合物可在合中間產物或起始物質。基團R2至 124938.doc -23 - 200829258 現將更密切地定義上文及下文中用以描述本發明化合物之一些術語。術語i素表示選自由F、cn、Br及I組成之群的原子。術语C1-n烧基，其中η可具有2至18之值，表示具有1至η 個C原子之飽和支鏈或非支鏈烴基。該等基團之實例包括甲基、乙基、正丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、正戊基、異戊基、新戊基、第三戊基、正己基、異己基等。術語Ch快基，其中η具有3至6之值，表示具有2至^個c 原子及CeC參鍵之支鏈或非支鏈烴基。該等基團之實例包括乙快基、1-丙炔基、2·丙炔基、丨—丁炔基、2_丁炔基、 3-丁炔基、1-戊炔基、戊炔基、3_戊炔基、4_戊炔基、卜己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基等。除非另外說明，否則炔基係在位置丨處經由c原子與分子之其餘部分連接。因此諸如^丙炔基、2_丙炔基、卜丁炔基等之術語相當於術語1-丙炔-丨_基、2-丙炔-^基、^丁炔_ 1-基等。此亦類似地應用於C2 n烯基。術語cNn烷氧基表示Cl-n烷基-0基團，其中Cin烷基係如上文所定義。該等基團之實例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基、第一丁氧基、正戊氧基、異戊氧基、新戊氧基、第三戊氧基、正己氧基、異己氧基等。術語Ch烷基羰基表示Cin烷基_c( = 〇)基團，其中烷基係如上文所定義。該等基團之實例包括甲基羰基、乙基 124938.doc -24- 200829258 羰基、正丙基羰基、異丙基羰基、正丁基羰基、異丁基幾基、第二丁基羰基、第三丁基羰基、正戊基羰基、異戊基罗炭基、新戊基魏基、第三戊基幾基、正己基幾基、異己基羰基等。術語(^-。環烷基表示具有3至η個C原子之飽和單、二、三或螺碳環基。該等基團之實例包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環壬基、環癸基、十氫秦基、雙環[3.2.1]辛基、螺[4.5]癸基、降呼基（norpinyi)、降宿基、降蒈基、金剛烷基等。術語c3 n環烷基較佳表示飽和單環基。術語Ch環烯基表示如上文所定義且另外具有至少一個不飽和C = C雙鍵之(^-。環烷基。術語(^-。環烷基羰基表示C3_n環烷基_c(=0)基團，其中 C3-n環烧基係如上文所定義。術語三（Ci_4烷基）矽烷基包含具有相同或兩個或三個不同烷基之矽烷基。術語二（Cw烷基）胺基包含具有相同或兩個不同Cw烷基之胺基。術語芳基較佳表示萘基或笨基，更佳表示苯基。術語雜芳基表示具有1至4個相同或不同之選自包含N、〇及S之群的雜原子之5或6員單環狀芳環。雜芳基較佳表示吡咯基、呋喃基、噻吩基、吡啶基或四唑基，或在各情況下1個或2個次甲基經氮原子置換之吡咯基、呋喃基、σ塞吩基或吼唆基。 124938.doc -25- 200829258 除非另外說明，否則上文及下文所用其中環基（例如笨環）之取代基之鍵指向環基之中心的結構式中之命名法表示該取代基可結合至該環基中具有Η原子之任何自由位置。本發明之化合物可使用大體上已知之合成方法獲得。化合物較佳由以下根據本發明於下文中更詳細描述之方法獲得。 & 本發明之式II之葡萄糖衍生物可藉由添加呈有機金屬化合物形式之所要苄基苯化合物自D_葡糖酸内酯或其衍生物合成（流程1)。程1 ·使金屬有機化合物添加至葡糖酸内g旨中It is especially preferred to have the meaning given by the formulas 1.1 a a to I.lc. , R 8d and R 1 to R 5 are as defined above and below k c 3 · 3 alkyl or benzyl, especially meaning H, B, chlorine or desert 'in particular means cyano or bromine; and 8 (1 independently of each other means H, Ci 4 alkylcarbonyl is represented by hydrazine, methylcarbonyl, ethylcarbonyl or as defined above. The compounds may be intermediates or starting materials. Groups R2 to 124938.doc -23 - 200829258 will now be more Some terms used above to describe the compounds of the invention are defined in close proximity. The term i represents an atom selected from the group consisting of F, cn, Br and I. The term C1-n alkyl, wherein n may have 2 A value of 18 represents a saturated branched or unbranched hydrocarbon group having 1 to η C atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl. , a second butyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a third amyl group, a n-hexyl group, an isohexyl group, etc. The term Ch fast radical, wherein η has a value of 3 to 6, indicating a branched or unbranched hydrocarbon group having 2 to c atoms and a CeC bond. Examples of such groups include ethyl, 1-propynyl, 2, propynyl, -butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, pentynyl, 3-pentynyl, 4-pentynyl, albynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc. Unless otherwise stated, an alkynyl group is attached to the remainder of the molecule via a c atom at a position 。. Thus, for example, propynyl, 2_ The terms propynyl, butynyl and the like correspond to the terms 1-propyne-fluorenyl, 2-propyne-yl, butyl-1-enyl, etc. This applies analogously to C2 n-alkenyl. The term cNn alkoxy denotes a Cl-nalkyl-0 group wherein the Cin alkyl group is as defined above. Examples of such groups include methoxy, ethoxy, n-propoxy, isopropoxy , n-butoxy, isobutoxy, second butoxy, first butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, third pentyloxy, n-hexyloxy, dissimilar The oxy group, etc. The term Ch alkylcarbonyl denotes a Cin alkyl-c(= 〇) group, wherein the alkyl group is as defined above. Examples of such groups include methylcarbonyl, ethyl 124938.doc -24- 200829258 carbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butyl Base, isobutyl group, t-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarboyl, neopentylwei, tripentyl, n-hexyl, Isohexylcarbonyl, etc. The term (^-.cycloalkyl) denotes a saturated mono-, di-, tri- or spirocarbocyclyl group having 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, and ring. Pentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, decahydromethyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyi, Lowering base, norbornyl, adamantyl, etc. The term c3 n cycloalkyl preferably denotes a saturated monocyclic group. The term Ch cycloalkenyl denotes (^-.cycloalkyl) as defined above and additionally having at least one unsaturated C=C double bond. The term (^-.cycloalkylcarbonyl represents C3_ncycloalkyl-c(=0) a group wherein the C3-n cycloalkyl group is as defined above. The term tris(Ci_4 alkyl)decylalkyl comprises a decyl group having the same or two or three different alkyl groups. The term di(Cw alkyl)amine The group includes an amine group having the same or two different Cw alkyl groups. The term aryl preferably represents a naphthyl group or a stupid group, more preferably a phenyl group. The term heteroaryl group means having 1 to 4 identical or different selected from the group consisting of a 5- or 6-membered monocyclic aromatic ring of a hetero atom of the group N, 〇 and S. The heteroaryl group preferably represents pyrrolyl, furyl, thienyl, pyridyl or tetrazolyl, or in each case 1 Or a pyrrole group, a furyl group, a σ-septyl group or a fluorenyl group substituted with a nitrogen atom by a nitrogen atom. 124938.doc -25- 200829258 Unless otherwise stated, a ring group (such as a stupid ring) is used above and below. The nomenclature of the substituent of the substituent to the center of the ring group indicates that the substituent can be bonded to the ring group Any free position of a ruthenium atom. The compounds of the present invention can be obtained using generally known synthetic methods. The compounds are preferably obtained by the following process in accordance with the present invention as described in more detail below. & Glucose Derivatives of Formula II of the Invention It can be synthesized by adding a desired benzylbenzene compound in the form of an organometallic compound from D_gluconolactone or a derivative thereof (Scheme 1). Process 1 · Adding a metal organic compound to gluconic acid

根據流程1之反應較佳自經鹵化之通式IV之苄基苯化合物起始進行’其中Hal表示氯、溴或碘。流程1中之Rl表示氯基或可隨後轉化為氰基之基團，諸如氯、溴、羧基、羧酸i旨、羧酿胺或其衍生物、硼或矽烷基、經保護或經遮蔽之酸g能基（諸如縮駿或嗟唑）或經保護或經遮蔽之胺基官能基（諸如硝基）。苄基苯（v)之格林納試劑（Grignard 124938.doc -26 - 200829258 咖㈣）或鈒試劑可自相應氣化、漠化或蛾化之节基苯以經由所謂金屬交換反應或藉由將金屬插人至碳^鍵中製備。用以合成相應裡化合物v之鹵素_金屬交換可用有機鐘化合物（諸如正、第二或第- 正弟次弟二丁基链）進行。類似鎮化 ^物亦可在無或有加成鹽(諸如可加速金屬化過程之氣化鐘）存在下以合適格林誠劑（諸如丨臭化或氯化異丙基鎮或第：丁基鎂’或二異丙基鎂或二第二丁基鎂)藉由二屬父換產生；特定金屬交換有機鎭化合物亦可自合適前驅物當場產生（參見例如c/z_ 2〇〇4，"6，3M6_3399 及如gw. CA㈣· 2006’ 77(§，165_169及其中引用之參考文獻）。另外，同樣可使用由將（例如）氯化或溴化丁基鎂或氯化或漠化異丙基鎮與丁基鐘組合產生之有機鎮化:物之^ 根型複合物（參見例如如g⑽2〇〇〇，"2 2594 25% 及办⑽Ze". 2001，仏484 1-4844及其中引用之參考文獻）。鹵素-金屬交換反應較佳在4(rc與」〇(rc之間，、其較佳在lot與-80°c之間，在惰性溶劑或其混合物（諸如 ***、二噁烷、四氫呋喃、甲苯、己烷、二甲亞甲烷或其混合物）中進行。因此獲得之鎂或鋰衍生化合物可視情況與金屬鹽（諸如三氯化鈽、氯化鋅或溴化辞、氯化銦或溴化銦）進行金屬交換以形成適於添加之替代有機金屬化合物（V)。或者，有機金屬化合物v亦可藉由將金屬 ***齒芳族化合物IV之碳-鹵鍵中製備。對於該轉化而言，鋰或鎂為合適元素金屬。可在-8〇至l〇〇t：，較佳·7〇至 4 0 C範圍内之溫度下在諸如***、二噁烷、四氫呋喃、甲 124938.doc •27- 200829258The reaction according to Scheme 1 is preferably carried out starting from the halogenated benzylbenzene compound of the formula IV wherein Hal represents chlorine, bromine or iodine. R1 in Scheme 1 represents a chloro group or a group which can be subsequently converted to a cyano group, such as chlorine, bromine, carboxyl, carboxylic acid, carboxy amide or a derivative thereof, boron or decyl, protected or masked. An acid g-energy group (such as a tortoise or carbazole) or a protected or masked amine functional group (such as a nitro group). Benzylbenzene (v) Grignard reagent (Grignard 124938.doc -26 - 200829258 coffee (4)) or hydrazine reagent can be from the corresponding gasification, desertification or moth basal benzene to pass the so-called metal exchange reaction or by Metal is inserted into the carbon ^ bond to prepare. The halogen-metal exchange for synthesizing the corresponding compound v can be carried out using a compound of a clock (such as a positive, second or first-thoracic dibutyl chain). Similar sedatives may also be in the presence of a suitable Greene agent in the absence or presence of an addition salt (such as a gasification clock that accelerates the metallization process) (such as odor or isopropyl chloride or butyl: Magnesium or diisopropylmagnesium or dibutylmagnesium is produced by the substitution of two genera; specific metal-exchanged organic ruthenium compounds can also be produced on the spot from suitable precursors (see for example c/z_ 2〇〇4,&quot ;6,3M6_3399 and as gw. CA(iv) · 2006' 77 (§, 165_169 and references cited therein). Alternatively, it is equally possible to use, for example, chlorinated or butylmagnesium bromide or chlorinated or desertified Organic towns produced by the combination of propyl and butyl rings: root complexes (see for example g(10)2〇〇〇, "2 2594 25% and Office (10)Ze". 2001, 仏484 1-4844 and References cited). The halogen-metal exchange reaction is preferably between 4 (rc and "〇 (rc, preferably betweenlot and -80 °c) in an inert solvent or a mixture thereof (such as diethyl ether, two Oxygen, tetrahydrofuran, toluene, hexane, dimethylmethane or a mixture thereof), thus obtaining magnesium or lithium The bio-compound may optionally be metal exchanged with a metal salt such as antimony trichloride, zinc chloride or bromide, indium chloride or indium bromide to form an alternative organometallic compound (V) suitable for addition. Alternatively, organic The metal compound v can also be prepared by inserting a metal into the carbon-halogen bond of the tooth aromatic compound IV. For the conversion, lithium or magnesium is a suitable elemental metal. It can be in the range of -8 〇 to l 〇〇 t: Between 7 〇 and 40 ° C at temperatures such as diethyl ether, dioxane, tetrahydrofuran, A 124938.doc • 27- 200829258

i / 、己院、二甲亞硬及其混合物之溶劑中實現該***。在無自發反應發生之情況下，先前活化金屬可為必要的，諸如用1，2二溴乙烷、碘、三甲基矽烷基氣、乙酸、鹽酸及/ 或超聲波加以處理。較佳在之間，尤其較佳在0至-80°C的溫度下，在惰性溶劑或其混合物中，進行將金屬有機化合物v添加至葡糖酸内酯或其衍生物（VI)中以獲得式II化合物。所有上述反應儘管在諸如氬及氮之惰性氣氛下執行較佳，但均可在空氣中進行。金屬化作用及/ 或偶合反應亦可在能夠達到高交換率之微型反應器及/或 U型混合态中進行；例如類似於描述於w〇几中之方法用於將經金屬化之苯基V添加至經適當保護之葡糖酸内㈣中之合適溶劑為(例如)***、二曱氧基乙烷、本、甲苯、二氯甲烷、己烷、四氫呋喃、二噁烷、N_甲基吼略㈣及其混合物。可在無任何其他佐劑存在下或在緩慢反應偶合搭配物之情況下，在諸如BF3*OEt2或Me3sicl 之促進劑存在下進行該加成反應（參見M. Schl0ssThis insertion is achieved in a solvent of i / , hexagram, dimethyl sulfite and mixtures thereof. In the absence of a spontaneous reaction, a previously activated metal may be necessary, such as treatment with 1,2 dibromoethane, iodine, trimethylsulfonium alkyl, acetic acid, hydrochloric acid, and/or ultrasonics. Preferably, the metal organic compound v is added to the gluconolactone or a derivative (VI) thereof in an inert solvent or a mixture thereof, preferably at a temperature of from 0 to 80 ° C. A compound of formula II is obtained. All of the above reactions, although preferably carried out under an inert atmosphere such as argon and nitrogen, can be carried out in air. Metallization and/or coupling reactions can also be carried out in a microreactor and/or U-type mixed state capable of achieving high exchange rates; for example, similar to the method described in the above, for the metallization of phenyl groups Suitable solvents for the addition of V to the appropriately protected gluconic acid (IV) are, for example, diethyl ether, dimethoxyethane, benzo, toluene, dichloromethane, hexane, tetrahydrofuran, dioxane, N-methyl Strategy (4) and its mixture. The addition reaction can be carried out in the presence of a promoter such as BF3*OEt2 or Me3sicl in the absence of any other adjuvant or in the presence of a slow reaction coupling partner (see M. Schl0ss).

Organometallics in Synthesis τ u m.i ymnesis, j〇hn Wiley & Sons,Organometallics in Synthesis τ u m.i ymnesis, j〇hn Wiley & Sons,

Chichester/New Y〇rk/Brishηnt* nsbane/T〇r〇nto/Singapore，1994)。流程^中之取代基μ之較佳定義為节基、經取代之节基、烯丙基、三縣㈣基，尤純㈣三甲基㈣基、三異丙基梦烧基、婦丙基、4 -甲羞. T虱基卞基及苄基。若兩個相鄰取代基R8連接於一起，|丨丨兮楚^ / 貝J该專兩個取代基較佳為亞苄基縮駿、4-甲氧基亞苄基縮醛、1 -内基、％酮之一部分或與經由丁烷之2及3位置與哌喃糖之相翻 <不目外P虱原子連接之2,3-二甲氧 124938.doc -28- 200829258 基-丁烯組成二噁烷。基團R，較佳表示氫、。丨_4烷基、烷基羰基或cN4烷基氧基羰基，尤其較佳表示氫、曱基或乙基。在將有機金屬化合物V或其衍生物添加至葡糖酸内 S旨VI中後引入基團R，。若尺，等於氫或c"烷基，則在諸如乙酸、甲烧石黃酸、甲苯石黃酸、硫酸、三氟乙酸或鹽酸之酸存在下用諸如甲醇或乙醇之醇或水處理反應溶液。製備氫化合物II後藉由使該化合物與醇在酸性條件下反應亦可連接RI。在安置R’期間，保護基尺8若在所使用之反應條件下不穩定則可裂解，產生相應質子化化合物，亦即R8等於H 之化合物II。可使用有機化學之標準轉化或至少由有機合成專題文獻 (尤其參見 J· March，Advanced Organic Reactions，Chichester/New Y〇rk/Brishηnt* nsbane/T〇r〇nto/Singapore, 1994). The substituent μ in the scheme ^ is preferably defined as a benzyl group, a substituted benzyl group, an allyl group, a three-county (tetra) group, a particularly pure (tetra)trimethyl(tetra)yl group, a triisopropylmethane group, and a propyl group. 4 - A shy. T 虱卞及 and benzyl. If two adjacent substituents R8 are linked together, the two substituents are preferably benzylidene, 4-methoxybenzylidene acetal, 1-in a part of a ketone, a part of a ketone, or a 2,3-dimethoxy- 12938.doc -28- 200829258 ke-butyl group linked to a p-halide atom via a 2 and 3 position of butane The alkene constitutes dioxane. The group R preferably represents hydrogen. The 丨4 alkyl group, the alkylcarbonyl group or the cN4 alkyloxycarbonyl group particularly preferably represents hydrogen, a fluorenyl group or an ethyl group. The group R is introduced after the organometallic compound V or a derivative thereof is added to the gluconic acid. If the ruler is equal to hydrogen or c"alkyl, the reaction solution is treated with an alcohol such as methanol or ethanol or water in the presence of an acid such as acetic acid, methicillin, toluene, sulfuric acid, trifluoroacetic acid or hydrochloric acid. . After the preparation of the hydrogen compound II, the RI can also be attached by reacting the compound with an alcohol under acidic conditions. During the placement of R', the protective substrate 8 can be cleaved if it is unstable under the reaction conditions employed, resulting in the corresponding protonated compound, i.e., compound II wherein R8 is equal to H. Standards for organic chemistry can be used or at least by organic synthesis (see especially J. March, Advanced Organic Reactions,

Reactions，Mechanisms，and Structure，第 4版，John Wiley & Sons，Chichester/New York/Brisbane/Toronto/Singapore， 1992及其中之參考文獻）已知之方法進行式IV之鹵芳族化合物之合成。更特定言之，使用過渡金屬及有機金屬化合物以合成芳族化合物已在不同專論中詳述（參見例如L. Brandsma, S.F. Vasilevsky, H.D. Verkruijsse, Application ofReactions, Mechanisms, and Structure, 4th Edition, John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1992 and references therein) are known methods for the synthesis of haloaromatic compounds of formula IV. More specifically, the use of transition metals and organometallic compounds to synthesize aromatic compounds has been detailed in various monographs (see for example L. Brandsma, S.F. Vasilevsky, H.D. Verkruijsse, Application of

Transition Metal Catalysts in Organic Synthesis，Springer-Transition Metal Catalysts in Organic Synthesis, Springer-

Verlag ， Berlin/Heidelberg, 1998 ； M. Schlosser，Verlag, Berlin/Heidelberg, 1998; M. Schlosser,

Organometallics in Synthesis, John Wiley & Sons， Chichester/New York/Brisbane/Tor onto/Singapore, 1994; P.J. Stang, F. Diederich, Metal-Catalyzed Cross-Coupling 似，Wiley-VCH，Weinheim，1997及其中引用之參考 124938.doc -29- 200829258 文獻）。在下文中所描述之合成策略以實例方式提供此之 α兒月另外’亦可使用相同合成方法使糖苦配基部分與已存在之略喃糖部分組合。Organometallics in Synthesis, John Wiley & Sons, Chichester/New York/Brisbane/Tor onto/Singapore, 1994; PJ Stang, F. Diederich, Metal-Catalyzed Cross-Coupling, Wiley-VCH, Weinheim, 1997 and references therein Reference 124938.doc -29- 200829258 literature). The synthetic strategy described hereinafter provides this by way of example. The same synthesis method can also be used to combine the saccharide ligand moiety with the existing oleochonose moiety.

Xml私2 · 一方基酉同片段之合成Xml Private 2 · Synthesis of one-party identical fragments

流程2展示可用於自苯甲醯氯及第二芳基起始應用弗瑞德-克來福特醯化（Friedel-Crafts acylation)條件或其變化形式合成式IV之鹵芳族化合物之前驅物化合物的製備。流程 2中之R1表示氰基或可隨後轉化為氰基之基團，諸如氯、溴、羧基、羧酸酯、羧醯胺或其衍生物、經保護或經遮蔽之醛官能基（諸如硫縮醛或噻唑）或經保護或經遮蔽之胺基官能基（諸如硝基）。該典型反應具有寬基質範疇且通常在以催化量或化學計量之量使用的催化劑（諸如A1Ch、 FeCh、碘、鐵、ZnCh、硫酸或三氟甲烷磺酸）存在下進行。亦可使用相應羧酸、酐、酯或苯甲腈替代苯曱醯氯。反應較佳在-30至12(TC，較佳30S10(rc之溫度下在諸如二氯甲烷及1，2-二氯乙烷之氯化烴中進行。然而，無溶劑反應或在微波爐中之反應亦為可能的。流程3 :使二芳基酮及二芳基甲醇還原為二芳基甲烧 124938.doc •30- 200829258Scheme 2 demonstrates the use of Friedel-Crafts acylation conditions or variants thereof to synthesize a halogenated aromatic compound precursor compound of Formula IV from benzamidine chloride and a second aryl group. Preparation. R1 in Scheme 2 represents a cyano group or a group which can be subsequently converted to a cyano group, such as chlorine, bromine, carboxyl, carboxylate, carboxamide or a derivative thereof, protected or masked aldehyde functional group (such as sulfur) Acetal or thiazole) or a protected or masked amine functional group such as a nitro group. This typical reaction has a broad matrix range and is typically carried out in the presence of a catalytic or stoichiometric amount of a catalyst such as A1Ch, FeCh, iodine, iron, ZnCh, sulfuric acid or trifluoromethanesulfonic acid. Instead of benzoquinone chloride, the corresponding carboxylic acid, anhydride, ester or benzonitrile can also be used. The reaction is preferably carried out in a chlorinated hydrocarbon such as dichloromethane and 1,2-dichloroethane at a temperature of -30 to 12 (TC, preferably 30 S10). However, no solvent reaction or in a microwave oven The reaction is also possible. Scheme 3: Reduction of diaryl ketone and diaryl methoxide to diaryl ketone 124938.doc • 30- 200829258

I、〇S〇2R、〇〇CR、00C0RI, 〇S〇2R, 〇〇CR, 00C0R

在流程3中，取代基R表示Cl_3烷基或芳基且…表示氰基或可隨後轉化為氰基之基團，諸如氯、溴 '羧基、鲮酸酯、羧醯胺或其衍生物、硼或矽烷基、經保護或經遮蔽之醛官能基（諸如縮醛或噻唑）或經保護或經遮蔽之胺基官能基（諸如硝基）。可以一個或兩個反應步驟自二芳基酮戍一方基曱醇起始得到二芳基甲烷。可以兩個步驟經由相應二苯基曱醇或以一個步驟將二芳基酮還原為二芳基曱院。在兩步變化形式中，用諸如金屬氳化物之還原劑將嗣還原以形成醇，該金屬氫化物諸如NaBH4、LiAIH4或iBU2A1H。在路易斯酸（諸如BF3*〇Et2、InC13或A1C13)或布忍^特酸（諸如鹽酸、硫酸、三氟乙酸或乙酸）存在下可用諸如玢 NaBH4或PhjiCIH之還原劑將所得醇轉化為所要二苯美甲 124938.doc -31 - 200829258 烷。例如可在路易斯酸或布忍斯特酸（諸如BF3*〇Et2、參 (五氟苯基）硼烷、三氟乙酸、鹽酸、氯化鋁或InCi〇存在下用矽烷（諸如EtJiH)、硼氫化物（諸如NaBH4)或鋁氫化物 (諸如UA1H4)進行自酮起始獲得二苯基甲烷之一步過程。較佳在-30至150。(；，較佳20至100。(：之溫度下，在諸如齒代烴（諸如二氯曱烷、曱苯、乙腈或其混合物）之溶劑中進行該等反應。另一可能合成方法為在諸如pd/木炭之過渡金屬催化劑存在下用氫還原。亦可能為根據沃夫_奇希諾 (Wolff-Kishner)或其變化形式之還原。首先用肼或i 物（諸如丨，2-雙（第三丁基二甲基石夕烷基）肼）將酮轉化為膝，其在強鹼性反應條件下裂解且加熱以形成二苯基甲烷及氛。可以-個反應步驟或在分離踪或其衍生物之後以兩個單獨反應步驟進行該反應。合適鹼包括（例如）於諸如乙二醇、甲苯、DMSO、2-(2-丁氧基乙氧基）乙醇或第三丁醇: 溶劑中之K〇H、NaOH或KOtBu;亦可能為無溶劑反應。可在20至25(TC之間，較佳為80至20(rc之間的溫度下進行該等反應。對於沃夫_奇希諾還原之鹼性條件之替代為此處亦可使用之發生在酸性條件下之克 1 水门秫遢原 (Ciemmensen reduction)。二芳基甲醇中之醇官能基亦可首先轉化為較佳離去基，諸如氣基、溴基、蟣&、乙酸酯基、碳酸酯基、磷酸酯基或硫酸酯基；隨後之 # 心成一方基甲烧之還原步驟在有機化學文獻中廣泛描述。流程4 :二芳基甲烷單元及其可能之前驅物化合物之合成 124938.doc -32- 200829258In Scheme 3, the substituent R represents Cl_3 alkyl or aryl and ... denotes a cyano group or a group which can be subsequently converted to a cyano group, such as chloro, bromo 'carboxyl, decanoate, carboxamide or a derivative thereof, Boron or nonylalkyl, protected or masked aldehyde functional groups such as acetals or thiazoles or protected or masked amine functional groups such as nitro groups. The diarylmethane can be obtained starting from a diaryl ketone oxime-based sterol in one or two reaction steps. The diaryl ketone can be reduced to the diaryl broth via two steps via the corresponding diphenyl decyl alcohol or in one step. In a two-step variation, the hydrazine is reduced with a reducing agent such as a metal halide to form an alcohol such as NaBH4, LiAIH4 or iBU2A1H. The resulting alcohol can be converted to the desired diphenyl using a reducing agent such as hydrazine NaBH4 or PhjiCIH in the presence of a Lewis acid such as BF3*〇Et2, InC13 or A1C13 or a benzoic acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid or acetic acid. Nail art 124938.doc -31 - 200829258 alkane. For example, decane (such as EtJiH), hydroboration can be used in the presence of a Lewis acid or a Brilliant acid such as BF3*〇Et2, gins(pentafluorophenyl)borane, trifluoroacetic acid, hydrochloric acid, aluminum chloride or InCi〇. A process such as NaBH4 or an aluminum hydride such as UA1H4 is carried out from the ketone to obtain diphenylmethane. Preferably, it is from -30 to 150. (;, preferably from 20 to 100. The reactions are carried out in a solvent such as a chiral hydrocarbon such as dichlorosilane, toluene, acetonitrile or a mixture thereof. Another possible synthesis is hydrogen reduction in the presence of a transition metal catalyst such as pd/charcoal. May be a reduction according to Wolff-Kishner or its variants. First use 肼 or i (such as 丨, 2-bis(t-butyldimethyl oxalate) 将) The ketone is converted to the knee, which is cleaved under strong alkaline reaction conditions and heated to form diphenylmethane and an atmosphere. The reaction can be carried out in two separate reaction steps after one reaction step or after separation or its derivative. Bases include, for example, such as ethylene glycol, toluene, DMSO, 2-(2-butyl) Ethyl ethoxy) ethanol or tert-butanol: K〇H, NaOH or KOtBu in a solvent; may also be a solvent-free reaction. Between 20 and 25 (TC, preferably 80 to 20 (rc) The reaction is carried out at a temperature of 4. The substitution of the basic conditions for the reduction of the Wolf_Chisinol is the Ciemmensen reduction which can also be used here under acidic conditions. Diarylmethanol The alcohol functional group may also be first converted to a preferred leaving group such as a gas group, a bromo group, a hydrazine group, an acetate group, a carbonate group, a phosphate group or a sulfate group; The reduction step of ketone is widely described in the organic chemistry literature. Scheme 4: Synthesis of diarylmethane units and their possible precursor compounds 124938.doc -32- 200829258

HalHal

Hal = Cl, Br, I，〇S〇2CF3, 〇S〇2p-Tol 步驟1 i素-金屬交換Hal = Cl, Br, I, 〇S〇2CF3, 〇S〇2p-Tol Step 1 i-metal exchange

MaHal、B(0H)2 步驟4MaHal, B(0H)2 Step 4

在流程4中，R1表示氰基或可隨後轉化為氰基之基團，諸如氯、溴、羧基、羧酸酯、羧醯胺或其衍生物、硼或矽烷基、經保護或經遮蔽之醛官能基（諸如縮醛或噻唑）或經保護或經遮蔽之胺基官能基（諸如硝基）。術語MAlkn表示 (^_3烷基且各取代基R彼此獨立地選自由Η、Ci_3烷基及Cw 124938.doc -33 - 200829258 烷氧基組成之群。流程4描述自金屬化苯基起始合成二芳基甲烷及其可能之前驅物化合物。可藉由與（例如）丁基鋰、函化異丙基鎖或二異丙基鎮之齒素-金屬交換反應或藉由將元素金屬***至幽·碳鍵中而自氯化、漠化或蛾化 t芳族化合物來合成經鋰或鎂取代之芳族化合物。可藉由與硼親電子劑(諸如蝴酸酯或其衍生物)反應而自該等金屬化苯基得到相應經删取代之化合物（諸如蝴酸、蝴酸醋或二 ⑦基芳基硼烷)。另外，亦可經由過渡金屬(例如鈀)催化之反應而自相應鹵化或假鹵化前驅物及二硼或硼烷化合物製備爛基化芳族化合物（參見例如办⑽—2〇〇3，第 4 895-4898頁及其中引用之參考文獻)。經鋰或鎂取代之苯 f化合物添加至苯甲駿（步驟3)及苯甲酸或其衍生物（諸如本甲n本甲醯胺（諸如Weinreb型）、苯甲猜或苯甲醯氯）（步驟4)中。該等反應可大體上在無其他過渡金屬催化劑或金屬交換為另一金屬（諸如鈽、銦或鋅）之情況下進 U 有時使用該等後述者替代者中之—者係有利的。可將 T基_酸藉助於㈣化劑而添加至苯甲时以提供個別二，彡基曱醇（參見例如抽.办被^/. 20(H，第343_350頁及二中引用之參考文獻）。此外，可使芳基蝴酸、其醋、 …土芳基硼烷或芳基二氟硼酸酯與由過渡金屬（諸如鈀）、其錯合物或鹽介導之苯甲醯氯偶合以產生二芳基酮。可使金屬化苯基與节基親電子試劑(諸如节基氯、节基漠或节基碟）反應以提供二芳基甲烧。链或鎮衍生化苯口物有利地但並不總是必要地在過渡金屬（諸如銅、 124938.doc -34- 200829258 鐵或鈀）存在下反應（參見例如〇rg· kii. 2001，3, 2871-2874 及其中引用之參考文獻）。由鋰或鎮經金屬交換為（例如）、錫、矽或鋅分別提供（例如）相應芳族_酸、錫烷、矽炫或鋅化合物，其可經歷與苄基親電子試劑（例如苄基鹵化物、碳酸酯、磷酸酯、磺酸酯或羧酸酯）之偶合。該反應係在過渡金屬（例如把、鎳、姥、銅或鐵）存在下進行（參見例如 reira/ze 办㈣ Ze"· 2004，第 8225-8228 頁及 Org. 2〇〇5,第4875_4878頁及其中引用之參考文獻）。流程5 :氰基部分之引入In Scheme 4, R1 represents a cyano group or a group which can be subsequently converted to a cyano group, such as chlorine, bromine, carboxyl, carboxylate, carboxamide or a derivative thereof, boron or a decyl group, protected or masked. An aldehyde functional group (such as an acetal or thiazole) or a protected or masked amine functional group (such as a nitro group). The term MAlkn denotes (^-3 alkyl and each substituent R is independently of one another selected from the group consisting of hydrazine, Ci_3 alkyl and Cw 124938.doc -33 - 200829258 alkoxy. Scheme 4 describes the initiation of synthesis from a metallated phenyl group a diarylmethane and its possible precursor compound, which can be exchanged with, for example, butyllithium, a functionalized isopropyl lock or a diisopropyl dentate-metal exchange or by insertion of an elemental metal Synthesis of a lithium or magnesium substituted aromatic compound from a chlorinated, desertified or moth-t-aromatic compound in a sec-carbon bond, which can be reacted with a boron electrophile such as a valerate or a derivative thereof. And the corresponding substituted metal compound (such as a butterfly acid, a citric acid or a bis 7 aryl borane) is obtained from the metallated phenyl groups. Alternatively, the reaction may be catalyzed by a transition metal (for example, palladium). Preparation of germinated aromatic compounds by halogenated or pseudohalogenated precursors and diboron or borane compounds (see, for example, Office (10)-2, 3, pages 4 895-4898 and references cited therein), substituted by lithium or magnesium Add benzene f compound to benzophenone (step 3) and benzoic acid or its derivatives Such as in the present case, the formamide (such as Weinreb type), benzac or benzamidine chloride (step 4). The reactions can be exchanged to another metal in the absence of other transition metal catalysts or metals. In the case of bismuth, indium or zinc), it may be advantageous to use one of those described later. The T-based acid may be added to the benzene by means of a (tetra) chemist to provide an individual. Mercaptosterol (see, for example, the pumping method.) (H, pp. 343-350 and references cited therein). In addition, aryl octanoic acid, its vinegar, ... aryl borane or aromatic The bis-difluoroborate is coupled with a benzamidine chloride mediated by a transition metal such as palladium, a complex or salt thereof to produce a diaryl ketone. The metallated phenyl group can be combined with a benzyl group electrophile (such as The reaction of a sulphur-based chlorine, a sulphate-based or a slab-based dish to provide a diaryl ketone. The chain or town-derived benzene ware is advantageously, but not always necessary, in a transition metal (such as copper, 124938.doc-34). - 200829258 Reaction in the presence of iron or palladium (see for example 〇rg. kii. 2001, 3, 2871-2874 and references cited therein Provided by lithium or cation metal exchange for, for example, tin, antimony or zinc, respectively, for example, corresponding aromatic-acid, stannane, xenon or zinc compounds, which can undergo benzyl electrophiles ( For example, coupling of benzyl halides, carbonates, phosphates, sulfonates or carboxylates. The reaction is carried out in the presence of a transition metal such as nickel, rhodium, copper or iron (see for example reira/ze) (4) Ze" 2004, pp. 8225-8228 and Org. 2〇〇5, pp. 4875_4878 and references cited therein.) Scheme 5: Introduction of the cyano moiety

MCN'MCN'

Hal =例如· Cl，Br,丨，〇S〇2PTo|, 〇S〇2CF3Hal = for example, Cl, Br, 丨, 〇S〇2PTo|, 〇S〇2CF3

XchS^Mh^XchS^Mh^

流程5顯示在合成目標分子之各階段將氰基殘基連接至 2心苯基之可能途徑。可經由適當氰基源（諸如氰化鈉、氰化鉀、氰化鋅或氰化銅）與齒化或假鹵化苯基之過渡金屬介導之偶合反應來引人氰基。合適催木厌）使用，以鹽（諸如氣化鈀、漠化鈀或乙酸鈀）或盥（例 :)膦:諸如三苯基膦、三第三丁基膦或dppf)或烯烴(諸如、苄基丙酮）之錯合物形式使用。活性催化劑可當場或在冰加至反應混合物之前產生。呈元素或鹽形式之添加劑 124938.doc -35- 200829258 (諸如鋅）可為有利的（參見巧⑽〜办⑽k". 2005, 46, 1849· 及 Tetrahedron Lett· 2005，46，181 5-1 81 8及其中引用之翏考文獻）。可經由鹵素金屬交換反應或藉由將個別金屬 ***至i鍵中自氯化、溴化或碘化化合物得到之相應鋅、鎂或鋰化合物與氰基親電子試劑（諸如對甲苯磺醯基氰化物、溴化氰或2-吡啶基氰酸酯）之反應為安置氰基官能基之另一可行方法（參見例如办Comm紙1996，3709-3714 及其中引用之參考文獻）。流程6 :自醛或羧酸衍生物引入氰基殘基Scheme 5 shows a possible route to attach a cyano residue to a 2-heart phenyl group at each stage of the synthesis of the target molecule. The cyano group can be introduced via a transition metal mediated coupling reaction with a suitable cyano source such as sodium cyanide, potassium cyanide, zinc cyanide or copper cyanide with a dentated or pseudohalogenated phenyl group. Suitable for use as a salt (such as gasified palladium, desertified palladium or palladium acetate) or hydrazine (for example: phosphine: such as triphenylphosphine, tri-tert-butylphosphine or dppf) or an olefin (such as The complex form of benzylacetone) is used. The active catalyst can be produced on-site or prior to the addition of ice to the reaction mixture. Additives in the form of elements or salts 124938.doc -35- 200829258 (such as zinc) may be advantageous (see Qiao (10) ~ Office (10) k " 2005, 46, 1849· and Tetrahedron Lett. 2005, 46, 181 5-1 81 8 and the references cited therein). a corresponding zinc, magnesium or lithium compound and a cyanoelectrophile (such as p-toluenesulfonyl cyanide) which can be obtained by a halogen metal exchange reaction or by inserting an individual metal into the i bond from a chlorinated, brominated or iodinated compound. The reaction of a compound, cyanogen bromide or 2-pyridyl cyanate is another possible method for the placement of a cyano functional group (see, for example, Comm Paper 1996, 3709-3714 and references cited therein). Scheme 6: Introduction of a cyano residue from an aldehyde or a carboxylic acid derivative

氰基之替代性引入為自醛或羧醯胺起始之合成（流程 6) 了將終式s能基自身以原樣、經保護或經遮蔽形式引入。酸：g能基之常用保護基為縮盤，但亦可使用其他保婼基（參見丁· W. Greene，P.G.M· Wuts，Protective Groups inAn alternative introduction of a cyano group is the initiation of synthesis from an aldehyde or carboxamide (Scheme 6). The final s-energy itself is introduced as it is, protected or masked. Acid: The common protecting group for the g energy base is the shrink disk, but other protecting groups can also be used (see D. W. Greene, P.G.M. Wuts, Protective Groups in

Organic Synthesis, John Wiley & Sons, Inc.5 New Y〇rk 124938.doc -36- 200829258 1999)°酸官能基之合適遮蔽為（例如）稀烴及嗟峻。可使用 ”（例如）甲酉夂、；辰鹽酸、多磷酸或π比咬-甲苯組合之（例如）胲將酸轉化為氰基官能基。可分離在該等反應條件下形成之中門物⑮ρ返後脫水以傳遞最終產物。亦可使用替代性胲試劑（諸如雙三氟乙酿基胲及NH20S03)且可在無其他試劑之情況下提供腈。其他適用試劑為（例如）於乙酸中之 NH4P〇4H2及硝基丙烷、三甲基矽烷基疊氮化物或s，s-二甲基硫化二醯亞胺。Organic Synthesis, John Wiley & Sons, Inc. 5 New Y〇rk 124938.doc -36- 200829258 1999) Suitable masking of the acid functional groups is, for example, a dilute hydrocarbon and a sulphur. The acid can be converted to a cyano functional group using, for example, formazan, hydrazine hydrochloride, polyphosphoric acid or π ratio bite-toluene, for example, hydrazine can be separated to form a smectic substance under such reaction conditions. 15ρ is post-dehydrated to deliver the final product. Alternative hydrazine reagents (such as bistrifluoroethyl hydrazide and NH20S03) can also be used and the nitrile can be provided without other reagents. Other suitable reagents are, for example, in acetic acid. NH4P〇4H2 and nitropropane, trimethyldecyl azide or s,s-dimethylsulfide diimide.

羧醯胺亦可為合適腈前驅物。可用脫水劑進行轉化，該等脫水劑諸如三氟乙酸酐、五氧化二磷、pocl3、ccu_膦組合、C13C0C1-胺組合、柏傑士試劑（Burgess reagent)、維爾斯邁爾試劑（VilSmeyer reagent)、S〇Cl2或三聚氯化氰。自相應單烧基化叛醯胺、魏酸、I旨或魏酸氯化物起始，亦可以一鍋式反應形成腈而無需分離任何中間物。流程7:自苯胺前驅物引入氰基殘基Carboxylamamine can also be a suitable nitrile precursor. Conversion can be carried out with a dehydrating agent such as trifluoroacetic anhydride, phosphorus pentoxide, pocl3, ccu_phosphine combination, C13C0C1-amine combination, Burgess reagent, VilSmeyer reagent ), S〇Cl2 or cyanuric chloride. Starting from the corresponding monoalkylation of tetamine, formic acid, I or teuric acid chloride, the nitrile can also be formed in a one-pot reaction without the need to separate any intermediates. Scheme 7: Introduction of a cyano residue from an aniline precursor

γ K： 1.)重氮化反應 2.)氰基-去-重氮化反應 (桑德邁爾反應）γ K: 1.) Diazotization reaction 2.) Cyano-de-diazonation reaction (Sandmeyer reaction)

X =例如Me, C〇〇H, C〇〇Alk, CH2〇H, CH2OAIk, CH2OAr,X = for example Me, C〇〇H, C〇〇Alk, CH2〇H, CH2OAIk, CH2OAr,

已充分確立之引入腈官能基之方法為利用氰化銅及可經由個別苯胺衍生物之重氮化反應得到之相應重氮化合物之所謂桑德邁爾反應（Sandmeyer reaction)。重氮化合物之合 124938.doc -37- 200829258 成及其隨後之氰基-去-重氮化反應已廣泛記錄於有機化學文獻中。為製備通式I化合物，在本發明之方法“中，使通式化合物：A well-established method of introducing a nitrile functional group is the so-called Sandmeyer reaction using copper cyanide and a corresponding diazonium compound which can be obtained by diazotization of individual aniline derivatives. The combination of diazo compounds 124938.doc -37- 200829258 and its subsequent cyano-de-diazonation reactions have been extensively documented in the organic chemistry literature. For the preparation of the compounds of the formula I, in the process of the invention, the compounds of the formula:

其中R’、R1至R5係如上文所定義且 RSa、R8b、R8e、R8d係如上文所定義且彼此獨立地表示 (例如）乙醯基、特戊醯基、苯甲醯基、第三丁氧基魏基、节基氧基羰基、三烷基矽烷基、烯丙基、苄基或經取代之苄基或在各情況下兩個相鄰基團、R8b、RSe、RSd係與亞苄基縮醛、二異丙基次矽烷基縮i同或亞異丙基縮酮或經由丁烯基團之2位及3位連接至哌喃糖環之氧原子且與其形成經取代--σ惡烧之2，3 -二甲氧基-丁稀基團組合，其可如上所述獲得，在路易斯酸或布忍斯特酸存在下與還原劑反應。反應之合適還原劑包括（例如）石夕烧（諸如三乙基石夕烧、三丙基石夕烧、三異丙基矽烷或二苯基矽烷）' 硼氫化鈉、氰基硼氫化鈉、硼氫化鋅、硼烷、氫化鋁鋰、氫化二異丁基紹或碘化釤。在無或有合適布忍斯特酸（諸如鹽酸、甲苯石黃酸、三氟乙酸或乙酸）或路易斯酸（諸如醚合三氟化哪、二氟甲磺酸三甲基矽烷酯、四氯化鈦、四氯化錫、三氟甲 124938.doc -38- 200829258 磺酸銃或碘化鋅）存在下進行還而中 c處 ’、視使用之還原劑及酸而疋，反應可在惊、急松 r ^ 1 Λ度下在啫如二氯甲 ^ ^ G崎、四氫呋喃、二噁烷、乙醇、水或其混合物之溶劑中進行試劑組合由（例如）三乙基矽烷，、口、之 % 口二鼠化硼組成，苴係Wherein R', R1 to R5 are as defined above and RSa, R8b, R8e, R8d are as defined above and independently of each other (for example) ethyl thiol, pentylene, benzamidine, third butyl Oxylopropion, benzyloxycarbonyl, trialkylalkyl, allyl, benzyl or substituted benzyl or in each case two adjacent groups, R8b, RSe, RSd and benzidine a acetal, a diisopropyl sulfenyl group or an isopropylidene ketal or an oxygen atom attached to the pipetose ring via the 2 and 3 positions of the butenyl group and forming a substituted - σ A combination of a non-fired 2,3-dimethoxy-butan group which can be obtained as described above and which is reacted with a reducing agent in the presence of a Lewis acid or a Brilliant acid. Suitable reducing agents for the reaction include, for example, sinter (such as triethyl sulphate, tripropyl sulphur, triisopropyl decane or diphenyl decane)' sodium borohydride, sodium cyanoborohydride, hydroboration Zinc, borane, lithium aluminum hydride, diisobutyl hydride or cesium iodide. In the absence or presence of a suitable Bronsted acid (such as hydrochloric acid, toluene, trifluoroacetic acid or acetic acid) or a Lewis acid (such as ether trifluoride, trifluoromethanesulfonate, tetrachlorinated Titanium, tin tetrachloride, trifluoromethyl 124938.doc -38- 200829258 sulfonium sulfonate or zinc iodide) can be carried out in the presence of c, 'depending on the use of reducing agent and acid, the reaction can be shocked, In a solvent such as trichloromethane, tetrahydrofuran, dioxane, ethanol, water or a mixture thereof, the reagent is combined by, for example, triethyl decane, and the like. % 二二鼠化硼组成,苴系

在鐵及6(TC之溫度下便利地於乙腈或二氣甲燒中使用。 =外，1可在過渡金屬催化劑(諸如飽/木炭或阮尼錄咖^咖)）存在下在諸如四氫β夫喃、乙酸乙醋、甲醇、乙酵、水或乙酸之溶劑中用於所述轉化。Conveniently used in acetonitrile or two gas at the temperature of iron and 6 (TC) = outside, 1 can be in the presence of a transition metal catalyst (such as saturated / charcoal or 阮尼录咖), such as tetrahydrogen The conversion is carried out in a solvent of beta cumin, ethyl acetate, methanol, ethyl acetate, water or acetic acid.

或者，為根據本發明之方&b)製備通式〗化合物，在通式III化合物中：Alternatively, a compound of the formula is prepared for the compound according to the invention & b), in the compound of the formula III:

其中R2至R5係如上文所定義且 R8a至R8d表示上文所定義之保護基（諸如醯基、烯丙基、芳基曱基、縮醛、縮酮或矽烷基）中之一者，且其可自如上文所述之式II化合物藉由（例如）還原獲得，使保護基裂解。例如，在0與120°C之間的溫度下，較佳在1〇與i〇(rCi 間的溫度下’在諸如三氟乙酸、鹽酸或硫酸之酸存在下或在諸如氫氧化鋰、氫氧化鈉或氫氧化鉀之鹼金屬驗存在下在例如水、異丙醇/水、乙酸/水、四氫呋喃/水或二α惡院/ 124938.doc -39- 200829258 水之水性溶劑中以水解方式裂解，或（例如）在碘三甲基矽烷存在下以質子惰性方式裂解所用之任何醯基保護基。較 k地在50與120 C之間的溫度下視情況在諸如乙酸之溶劑存在下藉由用諸如鹽酸之酸處理，或在〇與之間的度下視情況在諸如四氫呋喃或甲醇之溶劑存在下藉由用氳氧化鈉溶液處理來裂解三氟乙醯基。例士在〇與12〇 c之間的溫度下，較佳在⑺與！⑻。c之Wherein R 2 to R 5 are as defined above and R 8a to R 8 d represent one of the protecting groups defined above, such as a decyl group, an allyl group, an aryl fluorenyl group, an acetal, a ketal or a decyl group, and It can be obtained, for example, by reduction of a compound of formula II as described above, to cleave the protecting group. For example, at a temperature between 0 and 120 ° C, preferably at a temperature between 1 Torr and i 〇 (rCi in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in such as lithium hydroxide or hydrogen Alkali metal in the presence of sodium oxide or potassium hydroxide in the presence of water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or two alpha hospital / 124938.doc -39 - 200829258 aqueous solvent in water Pyrolysis, or any sulfhydryl protecting group used for cleavage in aprotic manner, for example, in the presence of iodotrimethylnonane, at a temperature between 50 and 120 C, as appropriate, in the presence of a solvent such as acetic acid The trifluoroethenyl group is cleaved by treatment with a sodium bismuth oxide solution in the presence of a solvent such as tetrahydrofuran or methanol, optionally with an acid such as hydrochloric acid. At temperatures between 〇c, preferably (7) and !(8).c

間的溫度下，在諸如三氟乙酸、鹽酸或硫酸之酸存在下在例如水、異丙醇/水、乙酸/水、四氫咬喃/水或二嚼燒/水之水性溶劑中以水解方式裂解，或（例如）在蛾三甲基石夕燒存在下以質子惰性方式裂解所用之任何㈣或縮嗣保護基。例如在諸如風乳化鐘、氫氧化納、碳酸钾或甲氧化納之双存在下在水、水性溶劑混合物或諸如甲醇或乙醇之低級醇中裂解三甲基矽烷基。 - 在水性溶劑或醇性溶劑中，諸如鹽酸、三氣乙酸或乙酸之酸μ適合的。對於在有機溶劑（諸如乙驗、四氫咬喃或一氣甲烧）中裂解而言，传用齑銨）亦適合。肖鼠化物成劑（諸如氟化四丁之=㈣’在G與之間的溫度下，但較佳在㈣60t 的周圍溫度下且在1至7巴，但較佳3至5巴之氫壓力下，在催化劑（諸如鈀/木炭）存在下，在人飞i力醇、乙醇、乙酸乙醋或冰乙酸) …1(諸如甲鹽酸），用（例如）氫以氫解方 “兄經添加酸（諸如飞^解卞基、曱氧基节基或节 124938.doc -40- 200829258 基氧基羰基。然而，較佳在苯甲醚存在下在三氟乙酸中裂解2,4-二甲氧基苄基。亦可在苯甲醚或五甲基苯存在下由三氯化硼或三氯化鋁裂解苄基。較佳地視情況使用諸如二氯甲烧、二噁烧、甲醇或乙鱗之溶劑，藉由用諸如三氟乙酸或鹽酸之酸處理或藉由用礙三甲基矽烷處理來裂解第三丁基或第三丁氧基羰基。Hydrolysis in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid in an aqueous solvent such as water, isopropanol/water, acetic acid/water, tetrahydroanthracene/water or diche/water Mode by cleavage, or for example, any (iv) or condensate protecting group used for a proticolytic cleavage in the presence of moths. For example, the trimethyldecyl group is cleaved in water, an aqueous solvent mixture or a lower alcohol such as methanol or ethanol in the presence of a double such as a wind emulsification clock, sodium hydroxide, potassium carbonate or sodium methoxide. - In an aqueous solvent or an alcoholic solvent, an acid μ such as hydrochloric acid, triacetic acid or acetic acid is suitable. For the cleavage in an organic solvent such as a test, tetrahydrogenated or a gas-fired, ammonium gluconate is also suitable.鼠化物化物 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( In the presence of a catalyst (such as palladium / charcoal), in the human fly alcohol, ethanol, ethyl acetate or glacial acetic acid) ... (such as methyl HCl), with hydrogen, for example, hydrogen An acid (such as a fluorenyl group, a fluorenyloxy group or a nodal 124938.doc -40-200829258 oxycarbonyl group. However, it is preferred to cleave 2,4-dimethoxy in trifluoroacetic acid in the presence of anisole. Benzyl. The benzyl group can also be cleaved from boron trichloride or aluminum trichloride in the presence of anisole or pentamethylbenzene. Preferably, such as dichloromethane, dioxane, methanol or butyl scale, is used. The solvent is cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with trimethyldecane to cleave the tributyl or tert-butoxycarbonyl group.

在上文所述之反應中，在反應期間可由在反應之後再次裂解之習知保護基保護所存在之任何反應性基團（諸如乙块基、羥基、胺基、烷基胺基或亞胺基）。舉例而言，乙炔基之保護基可為三烷基矽烷基（諸如三甲基矽烷基及三異丙基矽烷基）或二烷基_羥基甲基（諸如2_ 羥基異丙-2-基）。 γ 工、，平、丞丫 I、三甲基矽烷基、乙醯基、三苯甲基、苄基或四氫哌喃基。胺基、烧基胺基或亞胺基之保護基可為（例如）甲酿基、乙酿基、2氟乙醯基、乙氧基縣、第三τ氧基幾基、节基氧基幾基、节基、曱氧基节基或2,4_二此外，可將所獲得之通式ϊ化合物解析為如上文所提及之其對映異構體及/或非對映異構體。因&，例如順式/反式混合物解析為其順式及反式異構體 :至少1個光學活性碳原子之化合物分離為其對映異構 ^ S析法將順式/反式混合物解析為」、…式異構體’可將以外消旋物形式存在之所獲得 124938.doc -41 - 200829258 之通式I化合物由1盛由本身已知之方法（參看Allinger N. L·及 Eliel Ε· L·於丨，τ〇 · · P cs in stereochemistry”，第 ό卷，Wiley I n t e r s c i e n c e，】q 71 士、、In the reactions described above, any reactive group present (such as an ethyl group, a hydroxyl group, an amine group, an alkylamine group or an imine) may be protected by a conventional protecting group which is cleaved again after the reaction during the reaction. base). For example, the protecting group for the ethynyl group can be a trialkyldecyl group (such as trimethyldecyl and triisopropyldecyl) or a dialkyl-hydroxymethyl (such as 2-hydroxyiso-2-yl) . γ, ,, 丞丫, 丞丫, trimethyl decyl, ethenyl, trityl, benzyl or tetrahydropyranyl. The protecting group for the amine group, the alkylamino group or the imido group may be, for example, a mercapto group, an ethyl ketone group, a 2-fluoroethenyl group, an ethoxy group, a third oxy group, a benzyloxy group. Further, the obtained oxime compound can be resolved to its enantiomer and/or diastereomer as mentioned above. Further, the obtained oxime compound can be resolved as mentioned above. body. Because &, for example, the cis/trans mixture resolves to its cis and trans isomers: the compound of at least one optically active carbon atom is separated into its enantiomers, the cis/trans mixture The compound of the formula I obtained in the form of the racemic form can be obtained from the form of the racemic form of 124938.doc -41 - 200829258 by a method known per se (see Allinger N. L. and Eliel). Ε·L·于丨, τ〇· · P cs in stereochemistry”, Dijon, Wiley I nterscience,] q 71 士,,

)为離為其光學對映體且可基於通式I 、、口物非，映異構體之物理·化學差異使用本身已知之方 ^ (例如）猎由層析法及/或分步結晶將具有至少2個不對稱反原子之通式1化合物解析為其非對映異構體，且若該等化合物以外消旌开彡4^ $式獲传’則隨後可將其解析為如上所提及之對映異構體。一較佳地藉由於對掌性相上之管柱分離或藉由自光學活性洛劑中再結晶或藉由與可與外消旋化合物(尤其酸及其活化何生物或醇)形成鹽或衍生物(諸如酯或醯胺)之光學活性物質反應且(例如)基於其可溶性差異分離因此獲得之鹽或衍生物之非對映異構混合物來分離對映異構體，同時可在合適試劑作用下自純非對映異構體鹽或衍生物釋放游離對 ^體。常用之光學活性酸為（例如）D•及[型之酒石酸或二苯甲醯基酒石酸、二鄰甲苯基酒石酸、頻果酸、扇桃酸、樟腦石只酉文麵胺酉夂、天冬胺酸或奎尼酸。光學活性醇可為 (例如）(+)或（-)-薄荷腦且醯胺中之光學活性醯基（例如）可為 (+ )-或（-)-蓋基氧基幾基。 ~ 此外，可將式I化合物轉化為其鹽，尤其為醫藥用途而轉化為與無機酸或有機酸之生理學上可接受之鹽。用於此目的之酸包括（例如）鹽酸、氫溴酸、硫酸、甲烷磺酸、磷酸、反丁烯二酸、丁二酸、乳酸、擰檬酸、酒石酸或順丁稀二酸。 124938.doc -42- 200829258 此外，可將所獲得之化合物轉化為混合物，（例如）與胺基酸，尤其與α-胺基酸（諸如脯胺酸或***酸）之1:1或 1:2混合物，其可具有尤其有利之特性，諸如高結晶度。Is to be known as the optical enantiomer and can be based on the physical/chemical differences of the formula I, the non-isomer of the mouth, using a known method (for example) by chromatography and/or fractional crystallization. A compound of formula 1 having at least 2 asymmetric anti-atoms is resolved to its diastereomer, and if such compounds are removed, then they can be resolved as described above. The enantiomers are mentioned. Preferably, by separation from the column on the palm phase or by recrystallization from the optically active agent or by salt formation with a racemic compound, in particular an acid and its activated organism or alcohol An optically active substance of a derivative such as an ester or a guanamine is reacted and, for example, a diastereomeric mixture of the salt or derivative thus obtained is separated based on its solubility difference to separate the enantiomer, while at the same time The free pair is released from the pure diastereomeric salt or derivative under the action. Commonly used optically active acids are, for example, D• and [types of tartaric acid or benzoyl tartaric acid, di-o-tolyl tartaric acid, frequency fruit acid, rutinic acid, camphor stone, glutamate, glutinous rice, winter Amino acid or quinic acid. The optically active alcohol can be, for example, (+) or (-)-menthol and the optically active thiol group in the guanamine can be, for example, a (+)- or (-)-captooxy group. Furthermore, the compound of formula I can be converted to its salt, especially for medical use, to a physiologically acceptable salt with an inorganic or organic acid. Acids for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or cis-succinic acid. 124938.doc -42- 200829258 Furthermore, the obtained compound can be converted into a mixture, for example with 1:1 or 1 with an amino acid, especially with an a-amino acid such as lysine or phenylalanine: 2 a mixture which may have particularly advantageous properties, such as high crystallinity.

有利地亦可使用隨後之實例中所述之方法獲得本發明之化合物，為此目的其亦可與來自文獻之為熟練技術者所已知之方法組合，例如以下文獻中所述之方法：WO ' 98/3 1697 > WO 01/27128 > WO 02/083066 、WOAdvantageously, the compounds of the invention may also be obtained by the methods described in the examples which follow, for which purpose they may also be combined with methods known to those skilled in the art, such as those described in the literature: WO ' 98/3 1697 > WO 01/27128 > WO 02/083066, WO

03/099836、WO 2004/063209、WO 2004/080990、WO 〇 2004/0131 18、WO 2004/052902、WO 2004/052903、WO 2005/092877、WO 06/010557、WO 06/018150、WO 06/037537、WO 06/089872、WO 2006/064033、WO 2007/0936 10及美國申請案 US 2003/01 14390。如已提及，本發明之通式I化合物及其生理學上可接受之鹽具有重要藥理學特性，尤其為對鈉依賴性葡萄糖共轉運體SGLT(較佳地SGLT2)之抑制作用。可如下研究新穎化合物之生物學特性：可在測試裝置中證明物質抑制SGLT-2活性之能力，其中用含有人類鈉葡萄糖共轉運體2(Genbank寄存編號 * NM_003 041)之編碼序列之cDNA的表現載體 . pZeoSV(Invitrogen，EMBL寄存編號 L36849)穩定轉染 CHO- K1細胞株（ATCC No. CCL 61)或其他HEK293細胞株（ATCC No. CRL-1573)(CHO-hSGLT2 或 HEK-hSGLT2)。該等細胞株以鈉依賴性方式將經14C標記之α-甲基-葡萄哌喃糖苷 (14C-AMG，Amersham)轉運至細胞内部。 124938.doc -43- 200829258 如下進行SGLT_2檢定：在HanTs F 12培養基（Bio Whittaker)中用10%胎牛血清及 250 pg/ml腐草黴素（zeocin)(Invitrogen)培養 CHO_hSGLT2 細胞，且在DMEM培養基中用10%胎牛血清及250 pg/ml腐草黴素（Invitrogen)培養HEK293-hSGLT2細胞。藉由用PBS 洗滌兩次且隨後用胰蛋白酶/EDTA處理使細胞自培養燒瓶剝離。在添加細胞培養基後，將細胞離心，再懸浮於培養基中且於Casy細胞計數器中計數。隨後將每孔40,000個細胞接種至經聚-D-離胺酸塗佈之白色96孔板上且在37°C、 5 % C02下培育隔夜。將細胞用250 μΐ檢定緩衝液（Hanks平衡鹽溶液，137 mM NaCl，5.4 mM KC1，2.8 mM CaCl2， 1.2 mM MgS04及 10 mM HEPES(pH 7·4)，50 pg/ml僅大黴素（gentamycin))洗滌兩次。隨後將250 μΐ檢定緩衝液及5 μΐ 測試化合物添加至各孔中且將板在恆溫箱中再培育1 5分鐘。將5 μΐ 10% DMSO用作陰性對照。藉由添加5 μΐ 14C-AMG(0.05 pCi)至各孔中起始反應。在37°C、5% C02下培育2小時後，將細胞再用250 μΐ PBS(20°C)洗滌且隨後藉由添加 25 μΐ 0·1 N NaOH溶解（在 37°C 下 5 min)。將 200 μΐ MicroScint20(Packard)添加至各孔中且在37°C下再繼續培育20 min。在此培育後，在Topcount(Packard)中使用14C閃爍程式量測所吸收之14C-AMG之放射性。為測定對於人類SGLT1之選擇性，開展類似測試，其中在 CHO-K1 或 HEK293 細胞中表現 hSGLTl 之 cDNA(Genbank 寄存編號 NM000343)而非 hSGLT2 cDNA。 124938.doc -44- 200829258 本發明之通式i化合物可（例如）具有低於1〇〇〇 nM，尤其低於200 nM，最佳低於50 nM之EC50值。鑒於其抑制SGLT活性之能力，故本發明之化合物及其相應醫藥學上可接受之鹽適於治療及/或預防性治療所有可受抑制SGLT活性（尤其SGLT_2活性）影響之彼等病狀或疾病。因此，本發明之化合物尤其適於預防或治療疾病（尤其為代謝病症）或病狀，諸如丨型及2型糖尿病、糖尿病併發症（諸如視網膜病、腎病或神經病、糖尿病足、潰瘍、大血官病變）、代謝性酸中毒或酮病、反應性低血糖、高胰島素血症、葡萄糖代謝障礙、抗胰島素症、代謝症候群、不同起因之血脂異常、動脈粥樣硬化及相關疾病、肥胖鬲i壓、慢性心臟哀竭、水腫及高尿酸血症。該等物質亦適於預防β_細胞退化，諸如胰腺卜細胞之細胞凋亡或壞死。該等物質亦適於改善或恢復胰腺細胞之功能性，且亦增加胰腺β-細胞之數量及大小。本發明之化合物亦可用作利尿劑或抗高血壓劑，且適於預防及治療急性腎衰竭。藉由投與本發明之化合物，可降低或抑制肝臟中脂肪之 /、$積ΧΚ。因此根據本發明之另一態樣，提供預防、減緩、延遲或治療由此需要之患者中歸因於肝臟脂肪異常積聚之疾病或病狀之方法，其特徵在於投與本發明之化合物 =醫藥組合物。歸因於肝臟脂肪異常積聚之疾病或病狀尤其係4自由一般脂肪肝、非酒精性脂肪肝（NAFL)、非酒精性脂肪變性肝炎（NASH)、營養過度誘發之脂肪肝、糖尿病性脂肪肝、酒精誘發之脂肪肝或毒性脂肪肝組成之群。 124938.doc -45 - 200829258 羊。之本發明之化合物（包括其生理學上可接受之鹽）適於預防或治療糖尿病，尤其1型及2型糖尿病，及/或糖尿病併發症。另外本务明之化合物尤其適於預防或治療超重、肥胖 (包括I類、II類及/或m類肥胖）、内臟型肥胖及/或腹型肥胖。03/099836, WO 2004/063209, WO 2004/080990, WO 〇 2004/0131 18, WO 2004/052902, WO 2004/052903, WO 2005/092877, WO 06/010557, WO 06/018150, WO 06/037537 WO 06/089872, WO 2006/064033, WO 2007/0936 10 and US Application US 2003/01 14390. As already mentioned, the compounds of the formula I according to the invention and their physiologically acceptable salts have important pharmacological properties, in particular the inhibition of the sodium-dependent glucose cotransporter SGLT, preferably SGLT2. The biological properties of the novel compounds can be studied as follows: The ability of the substance to inhibit SGLT-2 activity can be demonstrated in a test device, wherein the expression of the cDNA containing the coding sequence of human sodium glucose cotransporter 2 (Genbank accession number * NM_003 041) Vector. pZeoSV (Invitrogen, EMBL Accession No. L36849) stably transfected CHO-K1 cell line (ATCC No. CCL 61) or other HEK293 cell line (ATCC No. CRL-1573) (CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport 14C-labeled α-methyl-glucopyranoside (14C-AMG, Amersham) to the inside of the cells in a sodium-dependent manner. 124938.doc -43- 200829258 SGLT_2 assay was performed as follows: CHO_hSGLT2 cells were cultured in 10% fetal bovine serum and 250 pg/ml zeocin (Invitrogen) in HanTs F 12 medium (Bio Whittaker) in DMEM HEK293-hSGLT2 cells were cultured in medium with 10% fetal calf serum and 250 pg/ml phleomycin (Invitrogen). The cells were detached from the culture flask by washing twice with PBS and then treated with trypsin/EDTA. After the addition of the cell culture medium, the cells were centrifuged, resuspended in the medium and counted in a Casy cell counter. 40,000 cells per well were then seeded onto poly-D-lysine coated white 96-well plates and incubated overnight at 37 ° C, 5 % C02. The cells were treated with 250 μΐ assay buffer (Hanks balanced salt solution, 137 mM NaCl, 5.4 mM KC1, 2.8 mM CaCl2, 1.2 mM MgS04 and 10 mM HEPES (pH 7.4), 50 pg/ml gentamicin only) )) Wash twice. 250 μL assay buffer and 5 μΐ test compound were then added to each well and the plates were incubated for an additional 15 minutes in an incubator. 5 μΐ 10% DMSO was used as a negative control. The reaction was initiated by the addition of 5 μΐ 14C-AMG (0.05 pCi) to each well. After 2 hours of incubation at 37 ° C, 5% CO 2 , the cells were washed again with 250 μM PBS (20 ° C) and then dissolved by the addition of 25 μΐ 0·1 N NaOH (5 min at 37 ° C). 200 μM MicroScint20 (Packard) was added to each well and incubation was continued for another 20 min at 37 °C. After this incubation, the radioactivity of the absorbed 14C-AMG was measured using a 14C flash program in Topcount (Packard). To determine the selectivity for human SGLT1, a similar test was performed in which the cDNA of hSGLT1 (Genbank Accession No. NM000343) was expressed in CHO-K1 or HEK293 cells instead of the hSGLT2 cDNA. 124938.doc -44- 200829258 The compounds of the formula i of the invention may, for example, have an EC50 value of less than 1 〇〇〇 nM, especially less than 200 nM, optimally less than 50 nM. In view of its ability to inhibit SGLT activity, the compounds of the present invention and their corresponding pharmaceutically acceptable salts are suitable for the therapeutic and/or prophylactic treatment of all conditions which may be affected by inhibition of SGLT activity (especially SGLT 2 activity) or disease. Thus, the compounds of the invention are especially suitable for the prevention or treatment of diseases, especially metabolic disorders, or conditions, such as sputum and type 2 diabetes, diabetic complications such as retinopathy, nephropathy or neuropathy, diabetic foot, ulcers, large blood Official lesions), metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorders, insulin resistance, metabolic syndrome, dyslipidemia of different causes, atherosclerosis and related diseases, obesity Compression, chronic heart failure, edema and hyperuricemia. These substances are also suitable for preventing β-cell degeneration, such as apoptosis or necrosis of pancreatic cells. These substances are also suitable for improving or restoring the functionality of pancreatic cells and also increasing the number and size of pancreatic β-cells. The compounds of the present invention are also useful as diuretics or antihypertensive agents, and are suitable for the prevention and treatment of acute renal failure. By administering the compound of the present invention, the //$ accumulation of fat in the liver can be reduced or suppressed. Thus, according to another aspect of the present invention, there is provided a method of preventing, slowing, delaying or treating a disease or condition attributed to abnormal accumulation of hepatic fat in a patient in need thereof, characterized in that the compound of the present invention is administered = medicine combination. Diseases or conditions attributed to abnormal accumulation of liver fat, especially 4 free fatty liver, nonalcoholic fatty liver (NAFL), nonalcoholic steatosis hepatitis (NASH), hypertrophic induced fatty liver, diabetic fatty liver , a group of alcohol-induced fatty liver or toxic fatty liver. 124938.doc -45 - 200829258 Sheep. The compounds of the present invention, including their physiologically acceptable salts, are suitable for the prevention or treatment of diabetes, especially type 1 and type 2 diabetes, and/or diabetic complications. In addition, the compounds of the present invention are particularly suitable for the prevention or treatment of overweight, obesity (including class I, class II and/or m class obesity), visceral obesity and/or abdominal fatness.

VV

對於治療或預防而言實現相應活性所需之劑量通常視待才又/、之化合物、患者、疾病或病狀之性質及嚴重性及投藥之方法及頻率而定且由患者之醫生決定。適宜地，對靜脈内途徑而言劑量可為1至100 mg，較佳1至30 mg，且對經口途徑而言劑量可為1至1000 mg，較佳1至100 mg，在各情況下均為一天投與丨至4次。為實現此目的，本發明之化合物可視情況連同其他活性物質，連同一或多種惰性習知載刎及/或稀釋劑一起調配，（例如）與玉米澱粉、乳糖、葡萄糖、微晶纖維素、硬脂酸鎂、聚乙烯吡咯啶酮、檸檬酉夂酒石酸、水、水/乙醇、水/甘油、水/山梨糖醇、水/ 聚乙二醇、丙二醇、十六醇十八醇、豸甲基纖維素或脂肪物質（諸如硬脂或其合適混合物）一起調配，以產生習知蓋倫製劑（galenic preparati〇n)，諸如普通㈣!或包衣錠劑: 膠囊劑、散劑、懸浮液或栓劑。本發明之化合物亦可結合其他活性物質-起使用，尤其用於/口療及/或預防以上提及之疾病及病狀。適於該等組口之其他活性物質包括（例如）加強本發明之sglt拮抗劑對於所提及之適應症巾之_者的治療效應及/或可使得本發 124938.doc •46- 200829258 明之SGLT拮抗劑之劑量減少之彼等物質。適於該組合之治療劑包括（例如）抗糖尿病劑（諸如二甲雙胍 (metformin))、磺醯基脲（例如格列本脲（glibenclamide)、甲本石萸丁脲（tolbutamide)、格列美脲（giimepiride))、那袼列奈（nateglinide)、諾和隆（repagHnide)、σ塞σ坐咬二g同（例如梵帝雅（rosiglitazone)、口比格列酮（pi〇giitaz〇ne))、ppAR_丫. 促效劑（例如GI 262570)及拮抗劑、ppAR-γ/α調節劑（例如 KRP297)、α-葡糖普轉抑制劑（例如醣祿（acarb〇se)、伏袼列波糠（voglibose))、DPPIV抑制劑（例如 LAF237、MK-43 1)、cx2-拮抗劑、胰島素及胰島素類似物、glp-Ι及GLp_ 1類似物（例如exendin-4)或支鏈澱粉。該列表亦包括蛋白質酪胺酸磷酸酶1之抑制劑，其為影響肝臟中去調節之葡萄糖產生之物質，諸如葡萄糖磷酸酶或果糖_1，6_雙磷酸酶、糖原磷酸化酶之抑制劑、胰高血糖素受體拮抗劑及石舞烯醇丙酮酸羧化激酶、肝糖合成酶激酶或丙酮酸脫氫激酶之抑制劑；降脂劑，諸如HMG_coA_還原酶抑制劑（例如斯伐他汀（simvastatin)、阿托伐他汀（atorvastatin))、纖維酸酉曰（例如本紮貝特（bezafibrate)、非諾貝特 (fenoHbrate))、菸鹼酸及其衍生物、ppAR-a促效劑、 PPAR-δ促效劑、ACAT抑制劑（例如阿伐麥布（avasimibe)) 或膽固醇吸收抑制劑（諸如依折麥布（ezetimibe));膽汁酸結合物質，諸如消膽胺（cholestyramine)，回腸膽汁酸轉運抑制劑’升HDL化合物，諸如CETP抑制劑或ABC1調節劑；或用於治療肥胖之活性物質，諸如諾美婷 124938.doc -47· 200829258 (sibutramine)或四氫利帕他汀（tetrahydrolip〇statin)、右芬說拉明（dexfenfluramine)、阿索開（axokine)、***素1受體之拮抗劑、MCH-1受體拮抗劑、MC4受體促效劑、NPY5 或NPY2拮抗劑或β3-促效劑（諸如SB-418790或AD-9677)及 5HT2c受體之促效劑。此外，與用於影響高血壓、慢性心臟衰竭或動脈粥樣硬化之藥物（諸如A-II拮抗劑或ACE抑制劑、ECE抑制劑、利展劑、β-阻斷劑、Ca-拮抗劑、中心作用抗高血壓劑、α_2-腎上腺素受體之拮抗劑、中性肽鏈内切酶之抑制劑、血小板聚集抑制劑及其他或其組合）的組合係合適的。血管收縮素II受體拮抗劑之實例為坎地沙坦西來替昔醋 (candesartan cilexetil)、洛沙坦鉀（potassium losartan)、甲石黃酸依普羅沙坦（eprosartan mesylate)、顯沙坦 (valsartan)、替米沙坦（telmisartan)、厄貝沙坦 (irbesartan)、EXP-3174、L-15 8809、EXP-3312、奥美沙坦酯（olmesartan medoxomil)、他索沙坦〇&8〇8&1^311)、1(：1[-3-671、GA-0113、RU-64276、EMD-90423、BR-9701 等。血管收縮素II受體拮抗劑較佳用於治療或預防高血壓及糖尿病併發症’通常與利尿劑（諸如氫*** (hydrochlorothiazide))組合。與尿酸合成抑制劑或排尿酸藥之組合適於治療或預防痛風。與GABA-受體拮抗劑、Na-通道阻斷劑、妥泰 (topiramat)、蛋白質-激酶C抑制劑、晚期糖基化終點產物 124938.doc -48- 200829258 抑制劑或酸糖$ 病併發症。原酶抑制劑之組合可用於治療或預防糖尿以上提及之組人彡 "5，其通常推蓆為〜之心有效地為最小劑量之属馮正常推薦劑量之至多ly/1。因此’在另一態樣中，、不&月係關於與上述作為組合搭配物之活性物質中之至少一 A#組合的本發明化合物或該化合物之生理學上可桩為々_ “扣、接又之孤的用途，其係用於製備適於治療或預防可藉由抑制納依賴性葡萄糖共轉運體影響之疾病或病狀之醫藥組合物。該等疾病或病狀較佳為代謝疾病’尤其為上文所列出之疾病或病狀中之一纟，最尤其為糖尿病或糖尿病併發症。本發明化合物或其生理學上可接受之鹽與另一活性物質組合使用可同時或以交錯時間（但尤其在短時間間隔内）發生。若將其同時投與，則將兩種活性物質一起給予患者；而若將其以交錯時間使用，則將兩種活性物質在小於或等於12小時，但尤其小於或等於6小時之時段内給予患者。因此，在另一態樣中，本發明係關於醫藥組合物，其包含本發明之化合物或該化合物之生理學上可接受之鹽及上述作為組合搭配物之活性物質中之至少一者，視情況連同一或多種惰性載劑及/或稀釋劑。因此’舉例而言’本發明之醫樂組合物包含本發明之式 1化合物或該化合物之生理學上可接受之鹽及至少一種血管收縮素II受體拮抗劑，視情況連同一或多種惰性載劑及/ 或稀釋劑之組合。 124938.doc -49- 200829258 ’及與其組合例如錠劑或膠，例如作為所本發明之化合物或其生理學上可接受之鹽之其他活性物質均可存在於一種調配物中，囊，或單獨存在於兩種相同或不同調配物中謂之組份套組。The dosage required to achieve the corresponding activity for treatment or prophylaxis will generally depend on the nature and severity of the compound, the patient, the disease or condition, and the method and frequency of administration, and will be determined by the patient's physician. Suitably, the dose may be from 1 to 100 mg, preferably from 1 to 30 mg, for the intravenous route, and from 1 to 1000 mg, preferably from 1 to 100 mg, for the oral route, in each case They all voted for 4 times a day. For this purpose, the compounds according to the invention may optionally be formulated together with other active substances, together with one or more inert conventional carriers and/or diluents, for example with corn starch, lactose, glucose, microcrystalline cellulose, hard Magnesium citrate, polyvinylpyrrolidone, lemon tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetostearyl alcohol, hydrazine methyl Cellulose or fatty substances such as stearin or a suitable mixture thereof are formulated together to produce a conventional galenic preparation, such as a common (four)! or coated lozenge: a capsule, a powder, a suspension or a suppository. . The compounds of the invention may also be used in combination with other active substances, especially for/oral therapy and/or prevention of the above mentioned diseases and conditions. Other active substances suitable for such a group of mouths include, for example, enhancing the therapeutic effect of the sglt antagonists of the invention on the mentioned indications and/or may result in the disclosure of 124938.doc • 46- 200829258 The dose of the SGLT antagonist is reduced by their substance. Therapeutic agents suitable for such combination include, for example, anti-diabetic agents (such as metformin), sulfonyl urea (e.g., glibenclamide, tolbutamide, glimepiride). (giimepiride)), nateglinide, repagHnide, σ σ 坐 sit two g (such as rosiglitazone, pi〇giitaz〇ne) , ppAR_丫. agonists (such as GI 262570) and antagonists, ppAR-γ/α modulators (such as KRP297), α-glucose inhibitors (such as acarb〇se, voltamidine) Voglibose, DPPIV inhibitors (eg LAF237, MK-43 1), cx2-antagonists, insulin and insulin analogs, glp-Ι and GLp-1 analogs (eg exendin-4) or amylopectin. The list also includes inhibitors of protein tyrosine phosphatase 1, which are substances that affect the production of deregulated glucose in the liver, such as glucose phosphatase or fructose-1,6-bisphosphatase, glycogen phosphorylase inhibition Agents, glucagon receptor antagonists and inhibitors of stone dance enol pyruvate carboxylase, glycogen synthase kinase or pyruvate dehydrogenase; lipid lowering agents, such as HMG_coA_reductase inhibitors (eg Simvastatin, atorvastatin, strontium strontium (such as bezafibrate, fenohbrate), niacin and its derivatives, ppAR-a Agent, PPAR-delta agonist, ACAT inhibitor (such as avasimibe) or cholesterol absorption inhibitor (such as ezetimibe); bile acid binding substance, such as cholestyramine An ileal bile acid transport inhibitor 'LDL compound, such as a CETP inhibitor or an ABC1 modulator; or an active substance for the treatment of obesity, such as Nome Ting 124938.doc -47· 200829258 (sibutramine) or tetrahydrolipa Statins Ydrolip〇statin), dexfenfluramine, axokine, cannabinoid receptor antagonist, MCH-1 receptor antagonist, MC4 receptor agonist, NPY5 or NPY2 antagonist Or an agonist of a β3-agonist (such as SB-418790 or AD-9677) and a 5HT2c receptor. In addition, with drugs for influencing hypertension, chronic heart failure or atherosclerosis (such as A-II antagonists or ACE inhibitors, ECE inhibitors, extenders, beta-blockers, Ca-antagonists, Combinations of centrally acting antihypertensive agents, antagonists of alpha 2 -adrenergic receptors, inhibitors of neutral endopeptidase, platelet aggregation inhibitors, and others, or combinations thereof, are suitable. Examples of angiotensin II receptor antagonists are candesartan cilexetil, potassium losartan, eprosartan mesylate, and salbutamol. (valsartan), telmisartan, irbesartan, EXP-3174, L-15 8809, EXP-3312, olmesartan medoxomil, toxasartan & 8 〇8&1^311), 1(:1[-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, etc. Angiotensin II receptor antagonist is preferably used for treatment or prevention Hypertension and diabetic complications are usually combined with diuretics (such as hydrochlorothiazide). Combination with uric acid synthesis inhibitors or uric acid drugs is suitable for the treatment or prevention of gout. With GABA-receptor antagonists, Na-channel resistance Bromide, topiramat, protein-kinase C inhibitor, advanced glycosylation end product 124938.doc -48- 200829258 Inhibitor or acid sugar disease complications. Combination of pro-enzyme inhibitors can be used for treatment or prevention The group mentioned in the above mentioned "diabetes" is "5, which is usually put as ~ Effectively, the minimum dose is von. The recommended dose is at most ly/1. Therefore, 'in another aspect, the formula is not combined with at least one of the above-mentioned active substances as a combination partner. The physiology of the compound of the invention or the compound can be used as a sputum, which is suitable for the treatment or prevention of diseases or diseases which can be affected by inhibition of a nano-dependent glucose co-transporter. Pharmaceutical compositions. The diseases or conditions are preferably metabolic diseases, especially one of the diseases or conditions listed above, most particularly diabetes or diabetic complications. The compounds of the invention or their physiology The use of a salt of a physiologically acceptable substance in combination with another active substance may occur simultaneously or at a staggered time (but especially within a short time interval). If administered simultaneously, the two active substances are administered together to the patient; When used in a staggered time, the two active substances are administered to the patient over a period of less than or equal to 12 hours, but especially less than or equal to 6 hours. Thus, in another aspect, the invention is A pharmaceutical composition comprising at least one of a compound of the present invention or a physiologically acceptable salt of the compound and the above-mentioned active substance as a combination partner, optionally with one or more inert carriers and/or diluted Thus, by way of example, the medical composition of the present invention comprises a compound of the formula 1 of the present invention or a physiologically acceptable salt of the compound and at least one angiotensin II receptor antagonist, optionally the same or A combination of various inert carriers and/or diluents. 124938.doc -49- 200829258 'and combinations thereof such as tablets or gums, for example as a compound of the invention or a physiologically acceptable salt thereof, may be present in a formulation, capsule, or separate There are two sets of components in the same or different formulations.

在上文及下文中，在每種情況下在結構式中不明確展示經基之Η原子。以下實例意欲說明本發明而非限制本發明。術語”室溫”及”周圍溫度"可互換使用且表示約2〇。^ 溫度。使用以下縮寫： iBu第三丁基 dba二亞苄基丙酮 DMF二甲基曱醯胺 DMSO二甲亞砜 NMP 甲基-2-σ比洛咬_ THF四氫吱喃起始化合物之製備：Above and below, the ruthenium atom of the radical is not explicitly shown in the structural formula in each case. The following examples are intended to illustrate and not to limit the invention. The terms "room temperature" and "ambient temperature" are used interchangeably and mean about 2 〇. ^ Temperature. The following abbreviations are used: iBu tert-butyl dba dibenzylideneacetone DMF dimethyl decyl DMSO dimethyl sulfoxide Preparation of NMP methyl-2-σ piroxime _ THF tetrahydrofuran starting compound:

實例IExample I

ΟΗ 3-溴-5·碘-2-甲基-苯甲酸將Ν-碘丁二酸亞胺（5.8 g)逐份添加至硫酸之冰***液中 (20 mL)。將所付混合物攪;拌4〇 min，隨後以使溶液溫度維持在5°C以下之速率添加溶解於硫酸（2〇 mL)中之2-溴-3-甲 124938.doc -50- 200829258 基-苯曱酸（5.0 g)。在5-10°C下將混合物再攪拌3 h，隨後溫至室溫隔夜。隨後，將混合物傾倒於碎冰（3 〇〇上且用乙酸乙自旨萃取所得溶液。用10% Na2S2〇3水溶液（2次）、水 (3次）及鹽水（1次）連續洗滌合併之萃取物。乾燥（MgS〇4)有機層之後，在減壓下將溶劑蒸發以得到固體。將該固體用 7 0 C溫水濕磨’藉由過濾與水分離且乾燥。在將該固體用少量***濕磨之後，過濾且乾燥，獲得呈白色固體狀之產物。產量：4.9 g(理論值之62%) 質譜（ESI-) : m/z=339/341 (Br) [M-H]-可類似於實例I獲得以下化合物： (1) 4 ->臭-5-換-2-甲基-苯甲酸ΟΗ 3-Bromo-5·iodo-2-methyl-benzoic acid Ν-iodosuccinate (5.8 g) was added portionwise to an ice-cold solution of sulfuric acid (20 mL). The mixture was stirred; mixed for 4 〇 min, then added to the 2-bromo-3-methyl 124938.doc -50-200829258 base dissolved in sulfuric acid (2 〇mL) at a rate to keep the solution temperature below 5 °C. - Benzoic acid (5.0 g). The mixture was stirred for a further 3 h at 5-10 ° C and then warmed to room temperature overnight. Subsequently, the mixture was poured onto crushed ice (3 Torr and the resulting solution was extracted with acetic acid B. The mixture was washed successively with 10% Na 2 S 2 3 aqueous solution (2 times), water (3 times) and brine (1 time). After the organic layer was dried (MgS 4), the solvent was evaporated under reduced pressure to give a solid. The solid was wet-ground with <RTIgt; After a small amount of diethyl ether was triturated, filtered and dried to give the product as a white solid. Yield: 4.9 g (62% of theory) Mass (ESI-): m/z=339/341 (Br) [MH]- The following compounds were obtained analogously to Example I: (1) 4 ->Smelly-5-exchange-2-methyl-benzoic acid

質譜（ESI·) ·· m/z=339/341 (Br) [M-H] (2) 2-溴-5-碘-3-甲基-苯甲酸Mass Spectrometry (ESI·) ·· m/z=339/341 (Br) [M-H] (2) 2-Bromo-5-iodo-3-methyl-benzoic acid

質譜（ESI) : m/z=339/341 (Br) [M-H] (3) 2-溴-5-碘-4·甲基-苯甲酸 124938.doc -51 - 200829258Mass Spectrometry (ESI): m/z = 339 / 341 (Br) [M-H] (3) 2-bromo-5-iodo-4-methyl-benzoic acid 124938.doc -51 - 200829258

Br QBr Q

OH 質譜（ESI·) : m/z=339/341 (Br) [M-H]· (4) (2 -漠-5-埃-4-甲氧基-苯基）-(4 -乙基-苯基）-曱酿]OH mass spectrometry (ESI·) : m/z = 339/341 (Br) [MH]· (4) (2 -Mo-5-A-4-methoxy-phenyl)-(4-ethyl-benzene Base) - brewing]

質譜（ESI + ) : m/z=445/447 (Br) [M+H] + 如以下實例II及III所述製備起始物質（2-溴-4-曱氧基-苯基）-(4-乙基-苯基）-甲酮。Mass Spectrum (ESI+): m/z = 445 / 447 (Br) [M+H] + </RTI> 4-ethyl-phenyl)-methanone.

實例IIExample II

(3-溴-5-蛾-2-甲基·苯基）_(4·乙基-苯基）_甲_ 將弘溴碘-2-甲基·苯甲酸（7.3 g)及S〇C12(70 mL)於與回机冷/旋為連接之燒瓶中組合。添加幾滴DMF且將混合物在回流下加熱i h。隨後，在減壓下濃縮反應溶液且將殘餘物溶解於二氯甲烧（8〇 mL)及乙基苯（15就）中。在冰浴中將所得溶液冷卻且逐份添加三氯化即·2 g)。隨後，移除冷部洽槽且在室溫下將反應混合物攪拌2 h。將反應混合物傾倒於碎冰上且分離出有機相。用二氣甲烷萃取水相 124938.doc -52- 200829258 且相繼用1 Μ鹽酸、NaHC〇3水溶液及鹽水洗滌合併之有機相。乾燥（硫酸鈉）有機相，移除溶劑且將殘餘物經珍析（環己烷/乙酸乙酯2〇: 1->9:1)。將純化產物自_ 層再結晶。 4基皱中產量：2.6 g(理論值之28%) 質譜（ESI + ) : m/z=429/431 (Br) [M+H] + 可類似於實例II獲得以下化合物： Γ' (1) (4->臭-5-蛾_2_甲基-苯基）·（4 -乙基-苯基）-甲酉^(3-Bromo-5-moth-2-methylphenyl)-(4·ethyl-phenyl)-methyl _ bromoiodo-2-methylbenzoic acid (7.3 g) and S〇C12 ( 70 mL) was combined in a flask connected to the cold/screw. A few drops of DMF were added and the mixture was heated under reflux for ih. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was dissolved in dichloromethane (8 mL) and ethylbenzene (15). The resulting solution was cooled in an ice bath and trichlorinated, i.e., 2 g) was added portionwise. Subsequently, the cold section was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured onto crushed ice and the organic phase was separated. The aqueous phase was extracted with dioxane methane 124938.doc -52- 200829258 and the combined organic phases were washed successively with 1 Μ hydrochloric acid, aqueous NaHCI3 and brine. The organic phase was dried (Na2SO4), solvent was evaporated and residue was purified (jjjjjjjj The purified product was recrystallized from the _ layer. Yield in 4 basis wrinkles: 2.6 g (28% of theory) Mass Spectrum (ESI + ): m/z = 429/431 (Br) [M+H] + The following compounds can be obtained analogously to Example II: Γ' (1 (4->Smelly-5-Moth_2_Methyl-phenyl)·(4-Ethyl-phenyl)-Methylhydrazine^

質譜（ESI+) : m/z=429/431 (Br) [Μ+Η] + (2) (2-溴-5-碘-3-甲基-苯基）-(4-乙基-苯基甲詞Mass Spectrum (ESI+): m/z = 429/431 (Br) [Μ+Η] + (2) (2-bromo-5-iodo-3-methyl-phenyl)-(4-ethyl-phenyl A word

Br 〇Br 〇

質譜（ESI + ) : m/z=429/431 (Br) [M+H] + (3) (2->臭-5-鐵-4-甲基-苯基）-(4 -乙基-苯基）-甲_Mass Spectrum (ESI + ) : m/z = 429/431 (Br) [M+H] + (3) (2->Smelly-5-iron-4-methyl-phenyl)-(4-ethyl -phenyl)-甲_

Br 〇Br 〇

質譜（ESI+) : m/z=429/431 (Br) [Μ+ΗΓ 124938.doc -53 - 200829258 (4) (2 -溴-4 -氟-笨基）-(4 -乙基-苯基）_甲酮Mass Spectrometry (ESI+): m/z = 429/431 (Br) [Μ+ΗΓ 124938.doc -53 - 200829258 (4) (2-Bromo-4-fluoro-phenyl)-(4-ethyl-phenyl) )_methanone

Br 〇Br 〇

質譜（ESI+) : m/z=307/309 (Br) [M+H] + 實例IIIMass Spectrum (ESI+): m/z = 307/309 (Br) [M+H] + EXAMPLE III

Br 〇Br 〇

(2-溴-4-甲氧基-苯基）-(4_乙基-苯基）_甲酮將甲氧化鈉（10.5 g)逐份添加至溶解於DMF(200 mL)中之 (2-溴-4-氟-苯基）-(4-乙基-苯基）-曱酮（43.0 g)中。將溶液攪拌隔仪’隨後添加另一份甲氧化鈉（5 _ 5 g)。再攪;拌3 h後，添加水且將所得混合物用乙酸乙酯萃取。乾燥（硫酸鈉）有機相，移除溶劑且將殘餘物經矽膠層析（環己烷/乙酸乙酯 20:1_>9:1)。產量：33.7 g(理論值之75%) 質譜（ESI + ) : m/z=319/321 (Br) [M+H] +(2-Bromo-4-methoxy-phenyl)-(4-ethyl-phenyl)-methanone Sodium methoxide (10.5 g) was added portionwise to dissolve in DMF (200 mL) (2 -Bromo-4-fluoro-phenyl)-(4-ethyl-phenyl)-fluorenone (43.0 g). The solution was stirred and then another sodium methoxide (5 _ 5 g) was added. After stirring for another 3 hours, water was added and the resulting mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulphate), solvent was removed and the residue was chromatographed (hexane/ethyl acetate 20:1_>9:1). Yield: 33.7 g (75% of theory) Mass Spectrum (ESI+): m/z=319/321 (Br) [M+H] +

實例IVExample IV

124938.doc 200829258 N-(4-溴·3-甲氧基-苯基）-乙醯胺將乙酸酐（13 mL)添加至4-溴-3 -甲氧基-苯基胺（25.0 g)於乙酸（100 mL)中之冰***液中。將混合物攪拌} 隨後用冰冷水（500 mL)稀釋。將沈澱藉由過濾分離，用水洗滌且在60°C下乾燥以得到產物。產量：30.0 g(理論值之99%) 貝谱（ESI ) · m/z=244/246 (Br) [M+H] +124938.doc 200829258 N-(4-Bromo-3-methoxy-phenyl)-acetamide Addition of acetic anhydride (13 mL) to 4-bromo-3-methoxy-phenylamine (25.0 g) In ice-cold solution in acetic acid (100 mL). The mixture was stirred} and then diluted with ice-cold water (500 mL). The precipitate was separated by filtration, washed with water and dried at 60 ° C to give a product. Yield: 30.0 g (99% of theory) Shell Spectrum (ESI) · m/z = 244/246 (Br) [M+H] +

實例VExample V

Ν-[4·漠-2-(4-乙基-苯甲酿基）_s•甲氧基-苯基】·乙醯胺將氧氣化鱗（17 mL)及氣化錫（IV)(5社）以使溫度維持於 35°C以下之速率連續添加至氺（4_漠_3_甲氧基-苯基> 乙醯Ν-[4·Imp-2-(4-ethyl-benzolic)_s•methoxy-phenyl]·acetamide will be oxygenated scale (17 mL) and vaporized tin (IV) (5 Continually added to 氺(4_漠_3_methoxy-phenyl) 乙醯 at a rate that maintains the temperature below 35 °C

胺（5.0 g)及4-乙基苯甲酸（4·4 g)於！，2•二氯乙烧中之懸浮液中。將：得混合物在回流溫度下加熱隔夜。隨後，將混合物用一氣甲院稀釋且傾倒於碎冰上。將水性混合物授掉3 〇 min後’將有機相分離且用於水中之跳Na〇H及水洗務。乾燥(硫酸鈉)有機相’移除溶劑且將殘餘物用甲醇濕磨以得到產物。產量：5.8g(理論值之75〇/〇) 質譜（ESI·) : m/z=374/376 (Br) [M-H]· 124938.doc -55- 200829258 實例νιAmine (5.0 g) and 4-ethylbenzoic acid (4·4 g) at! , 2• suspension in dichloroethane. The mixture was heated at reflux temperature overnight. Subsequently, the mixture was diluted with a gas chamber and poured onto crushed ice. After the aqueous mixture was removed for 3 〇 min, the organic phase was separated and used for the jump of Na〇H and water washing in water. The organic phase was dried (sodium sulfate) to remove solvent and the residue was triturated with methanol to give product. Yield: 5.8 g (75 理论 / 理论 of theory) Mass Spectrum (ESI·): m/z = 374/376 (Br) [M-H]· 124938.doc -55- 200829258 Example νι

3-溴-5-(4-乙基·苄基）_1_蛾-4-甲基-苯將（3-溴-5-碘-2-甲基-苯基H心乙基-苯基）_甲酉同（4·2 g)及三乙基矽烷（4.7 mL)於二氯甲烷（10 mL)及乙腈（28㈤“中之溶液以冰浴冷卻。隨後，經3 min逐滴添加三氟化硼乙醚錯合物（1.4 mL)。在周圍溫度下將溶液攪拌14 h，隨後添加25% KOH水溶液及二異丙基醚。分離有機相且將水相用二異丙㈣萃取三次。將合併之有機相用2㈣氧化卸溶液及鹽水洗滌且隨後乾燥（硫酸鈉）。蒸發溶劑後，將餘物經石夕膠層析（環己烷/乙酸乙酯1:〇_>1:1)。、產1 · 3·5 g(理論值之86〇/〇) 可類似於實例VI獲得以下化合物： )’臭5-(4-乙基_苄基）·卜峨—4-甲基_苯3-bromo-5-(4-ethyl-benzyl)_1-moth-4-methyl-benzene (3-bromo-5-iodo-2-methyl-phenyl H-ethyl-phenyl) _ formazan (4·2 g) and triethyl decane (4.7 mL) in dichloromethane (10 mL) and acetonitrile (28 (5)" solution in an ice bath. Subsequently, trifluoromethane was added dropwise over 3 min. Boron ether complex (1.4 mL). Stir the solution at ambient temperature for 14 h, then add 25% aqueous KOH solution and diisopropyl ether. Separate the organic phase and extract the aqueous phase three times with diisopropyl (tetra). The combined organic phases were washed with a 2 (4) oxidative effluent solution and brine and then dried (sodium sulfate). After evaporation of solvent, the residue was purified by chromatography (hexane/ethyl acetate: 〇 _ > 1:1 , production 1 · 3 · 5 g (theoretical 86 〇 / 〇) The following compounds can be obtained similarly to the example VI: ) 'odor 5-(4-ethyl-benzyl) · dip - 4-methyl _benzene

Br (2) 4_/臭-3_(4-乙基_苄基卜碘-5_甲基-苯Br (2) 4_/odor-3_(4-ethyl-benzylpyridinium-5-methyl-benzene

124938.doc -56- 200829258 (3) 4->臭-5_(4-乙基-卞基）-1-蛾-2-曱基-苯124938.doc -56- 200829258 (3) 4->Smelly-5_(4-ethyl-indenyl)-1-moth-2-mercapto-benzene

BrBr

質譜（ESI+) ·· m/z=432/434 (Br) [M+NH4] + (4) 4-溴-5-(4-乙基-苄基）-1-碘-2·甲氧基-苯Mass Spectrometry (ESI+) ·· m/z = 432/434 (Br) [M+NH4] + (4) 4-bromo-5-(4-ethyl-benzyl)-1-iodo-2·methoxy -benzene

BrBr

質譜（ESI + ) : m/z=448/450 (Br) [M+NH4] + 實例VIIMass Spectrum (ESI + ) : m/z = 448 / 450 (Br) [M+NH4] + EXAMPLE VII

N-[4-漠_2_(4_乙基节基）：甲氧基_苯基】_乙醯胺將硼氫化鈉（〇·i7 g)逐份添加至Nm(4_乙基_笨甲土）5甲氧基-苯基]-乙醯胺ο·25 g)於乙醇⑼社）中之料懸浮液中。移除冷卻浴槽且在周圍溫度下將溶液檀掉隨後’添加i M Na〇H水溶液（85虹）且將所得溶液酸tr萃:縮。將水添加至殘餘物中且將所得混合物用乙自夂乙酉日卒取。將合供古 — 有枝卒取物用鹽水洗滌，乾燥 124938.doc -57- 200829258 (NaJCU)且濃縮。將殘餘物溶解於三氟乙酸（2〇 mL)中且添加二乙基矽烷（4.3 mL)。在周圍溫度下將溶液攪拌隔夜且隨後傾倒於碎冰上。將所得混合物用乙酸乙酯萃取兩次。將合併之萃取物用鹽水洗滌，乾燥（硫酸鈉）且在減壓下濃縮。用甲醇處理殘餘物且分離所形成之沈澱。隨後將沈澱用二異丙基洗務且乾燥以得到所要產物。產量：2.8 g(理論值之89%) 質譜（ESI+) : m/z=362/364 (Br) [M+H] +N-[4-Mo _2_(4_Ethyl): methoxy-phenyl] acetamidine sodium borohydride (〇·i7 g) was added in portions to Nm (4_ethyl_ stupid) Methane) 5 methoxy-phenyl]-acetamide ο·25 g) in a suspension of ethanol (9). The cooling bath was removed and the solution was dropped at ambient temperature. Then an aqueous solution of i M Na〇H (85 rainbows) was added and the resulting solution was acid extracted: reduced. Water was added to the residue and the resulting mixture was taken up on day B. The collaterals were washed with saline, dried 124938.doc -57-200829258 (NaJCU) and concentrated. The residue was dissolved in trifluoroacetic acid (2 mL) and diethyl hexane (4.3 mL). The solution was stirred overnight at ambient temperature and then poured onto crushed ice. The resulting mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (sodium sulfate) and evaporated. The residue was treated with methanol and the formed precipitate was separated. The precipitate was then washed with diisopropyl and dried to give the desired product. Yield: 2.8 g (89% of theory) Mass Spectrum (ESI+): m/z = 362/364 (Br) [M+H] +

實例VIII nh2Example VIII nh2

4-溴-2-(4-乙基-苄基）-5-甲氧基-苯基胺將半濃鹽酸（5 mL)添加至N-[4-溴-2-(4-乙基-节基）_5_甲氧基-苯基]-乙醯胺（2.8 g)於異丙醇（20 mL)中之溶液中。 ii 在回流溫度下將溶液加熱8 h且隨後在減壓下濃縮以移除大部分醇。將NaHC〇3水溶液添加至殘餘物中且將所得混合物用乙酸乙S曰卒取兩次。將合併之有機萃取物用鹽水洗滌，乾燥（Na2S〇4)且濃縮以得到標題化合物。 * 產量：2·5 g(定量）質譜（ESI + ) ·· m/z=320/322 (Br) [M+H] +4-bromo-2-(4-ethyl-benzyl)-5-methoxy-phenylamine was added half-concentrated hydrochloric acid (5 mL) to N-[4-bromo-2-(4-ethyl- A solution of _5_methoxy-phenyl]-acetamide (2.8 g) in isopropanol (20 mL). Ii The solution was heated at reflux temperature for 8 h and then concentrated under reduced pressure to remove most of the alcohol. An aqueous solution of NaHC〇3 was added to the residue and the resulting mixture was taken twice with ethyl acetate. The combined organic extracts were washed with EtOAc EtOAc m. * Yield: 2·5 g (quantitative) Mass spectrometry (ESI + ) ·· m/z=320/322 (Br) [M+H] +

實例IX 124938.doc -58- 200829258Example IX 124938.doc -58- 200829258

NN

4-溴-2·(4-乙基-苄基）-5_甲氧基_苯甲腈將亞硝酸第三丁酯（1.1 mL)添加至CuCN(〇 36 g)KDMs〇 (3 mL)中之6(TC之溫熱溶液中。隨後，逐滴添加4_溴_2 — (4_ 乙基-苄基）-5-甲氧基-苯基胺（1〇 g)於DMS〇中之溶液且在 6〇°C下將所得溶液攪拌i h。冷卻至室溫後，藉由添加$ n 鹽酸水溶液酸化該溶液。用乙酸乙酯萃取所得混合物且將合併之萃取物乾燥（NajO4)。移除溶劑後，藉由矽膠層析法（環己烧/一氯曱烧3:1->1:3)純化殘餘物以得到標題化合物。產量：0.3 g(理論值之29%) 質譜（ESI+) : m/z=347/349 (Br) [M+NH4] +4-Bromo-2·(4-ethyl-benzyl)-5-methoxy-benzonitrile The third butyl nitrite (1.1 mL) was added to CuCN (〇36 g) KDMs(3 mL) 6 in the warm solution of TC. Subsequently, 4_bromo-2-(4-ethyl-benzyl)-5-methoxy-phenylamine (1〇g) was added dropwise to DMS. The solution was stirred for ih at 6 ° C. After cooling to room temperature, the solution was acidified by the addition of aqueous solution of EtOAc. The mixture was extracted with ethyl acetate and the combined extracts were dried (NajO4). After the solvent was removed, the residue was purified mjjjjjjjjjjjjjjjjjj ESI+) : m/z=347/349 (Br) [M+NH4] +

實例XExample X

1-溴-4-氰基-3-甲氧基-5-(4-乙基-苄基）_笨將KOtBu(11.8 g)添加至裝有攪拌棒及無水nmp(4〇㈤乙) 之燒瓶中且在氬氣氛下冷卻至-10t:。以使反應溫度維持於1CTC以下之速率添加（4-乙基-苯基）_乙酸乙酯（1〇1 g)及 124938.doc -59 - 200829258 、氰基-3,5-一氟-本（11.5 g)於NMP (40 mL)中之溶液。在室溫下攪拌1小時後，添加甲醇（50 mL)及1 M氫氧化鈉水溶液（39 mL)且在i〇(rc下將所得混合物攪拌隔夜。隨後/4、加4 Μ鹽酸水溶液（1〇〇 mL)且在i〇〇°c下將混合物再攪拌h。蒸發甲醇部分，將水（200 mL)添加至殘餘物中且將所得混合物用乙酸乙酯萃取。將合併之有機萃取物用水洗滌兩次，用鹽水洗滌兩次且乾燥（MgS〇4)。蒸發溶劑且將殘餘物用甲醇洗滌。將不可溶殘餘物藉由過濾分離且乾燥以得到白色產物。產量：10.0 g(理論值之58%) 質譜（ESI+) : m/z=330/332 (Br) [M+H] +1-Bromo-4-cyano-3-methoxy-5-(4-ethyl-benzyl)_ stupid KOtBu (11.8 g) was added to a stir bar and anhydrous nmp (4 〇 (5) B) The flask was cooled to -10 t: under an argon atmosphere. (4-Ethyl-phenyl)-ethyl acetate (1〇1 g) and 124938.doc -59 - 200829258, cyano-3,5-fluoro--this are maintained at a rate such that the reaction temperature is maintained below 1 CTC. (11.5 g) a solution in NMP (40 mL). After stirring at room temperature for 1 hour, methanol (50 mL) and 1 M aqueous sodium hydroxide (39 mL) were added and the mixture was stirred overnight at rt ( </ RTI> </ RTI> </ RTI> 〇〇mL) and the mixture was stirred for a further h. The methanol portion was evaporated, water (200 mL) was added to the residue and the mixture was extracted with ethyl acetate. Wash twice, wash twice with brine and dry (M.sub.4). The solvent is evaporated and the residue washed with methanol. The insoluble residue is isolated by filtration and dried to give white product. Yield: 10.0 g 58%) Mass Spectrum (ESI+): m/z = 330/332 (Br) [M+H] +

實例XIExample XI

1·溴·4-氰基-3-氟·5-(4-乙基-苄基）_苯將KOtBu(6.7 g)添加至裝有攪拌棒及無水nmp(30 mL)之燒瓶中且在氬氣氛下冷卻至-1 〇°C。以使溶液溫度維持於 1 0 C以下之速率添加（4 -乙基-苯基）·乙酸乙酯（5·6 §)及j· 溴-4-氰基-3,5·二氟-苯（6.4 g)於NMP(20 mL)中之溶液。在 1 〇 C下擾拌1小時後’將該溶液用1 Μ鹽酸水溶液中和且用乙酸乙酯萃取。乾燥（NaJO4)合併之萃取物且蒸發溶劑。將殘餘物溶解於THF(20 mL)中且用1 μ NaOH水溶液（80 124938.doc -60- 200829258 mL)處理。在室溫下攪拌隔夜後，將該溶液用4 M HQ溶液酸化且用乙酸乙酯萃取。將有機萃取物合併且乾燥 (NajO4)並蒸發溶劑。將殘餘物溶解於DMF(25 中且添加Κβ〇3(5·5 g)。在丨⑽^；下將所得混合物攪拌丨h。冷卻至室溫後，將混合物用丨M鹽酸水溶液中和且將所得混合物用乙酸乙料取。乾燥（Mg叫合併之有機萃取物且蒸發溶劑。藉由矽膠層析法（環己烷/乙酸乙酯⑴純化殘餘物。產量·· 4.8 g(理論值之51%) 質譜（ESI+) : m/z=317/319 (Br) [M] +1·Bromo·4-cyano-3-fluoro·5-(4-ethyl-benzyl)-benzene. KOtBu (6.7 g) was added to a flask equipped with a stir bar and anhydrous nmp (30 mL). Cool to -1 〇 ° C under an argon atmosphere. Add (4-ethyl-phenyl) ethyl acetate (5·6 §) and j· bromo-4-cyano-3,5·difluoro-benzene at a rate such that the solution temperature is maintained below 10 C. (6.4 g) a solution in NMP (20 mL). After stirring for 1 hour at 1 ° C, the solution was neutralized with a 1N aqueous solution of hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried (NaJO4) and evaporated. The residue was taken up in EtOAc (20 mL)EtOAcEtOAcEtOAc. After stirring overnight at room temperature, the solution was acidified with a 4 M HQ solution and extracted with ethyl acetate. The organic extracts were combined and dried (NajO4) and solvent evaporated. The residue was dissolved in DMF (25 and Κβ〇3 (5·5 g) was added. The mixture was stirred under 丨(10)^; 冷却h. After cooling to room temperature, the mixture was neutralized with 丨M aqueous hydrochloric acid and The resulting mixture was taken up in ethyl acetate. EtOAc (EtOAc m. 51%) Mass Spectrum (ESI+): m/z = 317/319 (Br) [M] +

實例XIIExample XII

將1-漠-4-氰基-3_氟-5_(4_乙基.笨基卜苯⑴〕添加 u I溴_4-氰基-3-環丁氧基-5-(4-乙基_苯基>苯有擾拌棒、K⑽U(0.5 g)及環丁醇（3 {) g)之燒瓶中。溫下將該溶液㈣隔夜，隨後添加另_份〖⑽咐2 :該溶液再攪拌5 h且隨後W ΜΗα水溶液中和。將混合物用乙酸乙酯萃取，將合併 ^ ^ ^ 、，钱相乾燥（硫酸^ 私除〉谷劑以得到標題化合物。產置：1.28 g(理論值之92〇/〇) 可類似於實例XII獲得以下化合物： 124938.doc -61 - 200829258 ⑴1-漠-4-氰基-5-(4_乙基_节基）_3_異丙氧基-苯Add 1-Imp-4-cyano-3_fluoro-5_(4-ethyl. Stupylbenzene (1)] to u Ibromo-4-cyano-3-cyclobutoxy-5-(4-ethyl Base _phenyl> benzene is disturbed in the flask, K(10)U (0.5 g) and cyclobutanol (3 {) g) in the flask. The solution is prepared overnight (4), then added another _ (10) 咐 2: The solution was stirred for a further 5 h and then neutralized with aqueous W.sub.4. The mixture was extracted with ethyl acetate. <RTI ID=0.0>> The theoretical value is 92 〇 / 〇) The following compounds can be obtained analogously to the example XII: 124938.doc -61 - 200829258 (1) 1-Molyl-4-cyano-5-(4-ethyl-phenyl)_3_isopropoxy -benzene

根據上述程序使用異丙醇替代環丁醇來製備該化合物 (2) 1-演-4-氰基_3_乙氧基_5_(4_乙基-节基苯The compound was prepared by using isopropanol instead of cyclobutanol according to the above procedure. (2) 1-Derivative-4-cyano_3_ethoxy_5_(4-ethyl-benzylbenzene)

NN

根據上述程序使用乙醇替代環丁醇來製備該化合物。 (3) 1-漠-4-氰基-5-(4-乙基-节基）_3_甲基硫基-苯This compound was prepared by replacing ethanol with cyclobutanol according to the above procedure. (3) 1-Mocol-4-cyano-5-(4-ethyl-nodal)_3_methylthio-benzene

在100°C下使用於二甲基甲醯胺中之甲硫化鈉製備該化合物。The compound was prepared at 100 ° C using sodium methane sulfide in dimethylformamide.

質譜（ESI+) : m/z=346/348 (Br) [M+H] + 實例XIII 124938.doc -62- 200829258Mass Spectrum (ESI+): m/z = 346/348 (Br) [M+H] + EXAMPLE XIII 124938.doc -62- 200829258

BrBr

1H(4-乙基苄基）-5-(l_甲氧基-D·葡萄糖哌喃+基）_2_ 甲基·苯將 iPrMgCl*LiCl 於 THF(lmol/L，10 mL)中之溶液逐滴添加至3-漠、- 5- (4 -乙基卞基）]-埃·4 -甲基-苯（3_5 g)於THF (20 mL)中之-6〇°C之***液中。經1 h之時間將溶液溫至-2(rc 且Ik後將2,3,4,6-肆-〇-(三甲基石夕烧基）-D-葡萄糖派喃酮 (4.8 g)於四氫吱喃（3 mL)中之溶液添加至該溶液中。將所得溶液緩慢溫至-5°C且攪拌6 h。用ΝΗβΙ水溶液中止該反應且將所得混合物用乙酸乙酯萃取。將合併之有機萃取物用鹽水洗滌且乾燥（硫酸鈉）。移除溶劑後，將殘餘物溶解於甲醇（30 mL)中且用甲烷磺酸（0·3 mL)處理。在4〇t下將溶液攪拌6 h且隨後藉由添加固體NaHC〇3來中和。在減壓下移除溶劑且將殘餘物溶解於乙酸乙酯中。將有機溶液用 K及1水洗條且乾燥（硫酸納）。移除溶劑後，使粗產物在無進一步純化之情況下接受還原。產量：4.2 g(粗產物）可類似於實例ΧΙΠ獲得以下化合物·· (1) K/臭…4-(4-乙基苄基）-2-U·甲氧基-D-葡萄糖哌喃-基）-5_甲基-苯 124938.doc -63 - 2008292581H(4-ethylbenzyl)-5-(l-methoxy-D·glucopyrane+yl)_2_methyl·benzene A solution of iPrMgCl*LiCl in THF (1 mol/L, 10 mL) It was added dropwise to a cold solution of 3-wet, -5-(4-ethylindenyl)]-e.4-methyl-benzene (3_5 g) in THF (20 mL). The solution was warmed to -2 (rc and 1k after 2 h of 2,3,4,6-肆-〇-(trimethyl-stone)-D-glucopyranone (4.8 g) in tetrahydrogen A solution of the oxime (3 mL) was added to the solution. The obtained solution was slowly warmed to -5 ° C and stirred for 6 h. The reaction was quenched with aqueous solution of ΝΗβΙ and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried (Na.sub.sub.sub.sub.sub.sub.sub.sub.sub. h and then neutralized by the addition of solid NaHC 〇 3. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic solution was washed with K and 1 water and dried (sodium sulfate). After the solvent, the crude product was subjected to reduction without further purification. Yield: 4.2 g (crude product) The following compound was obtained in the same manner as in Example · (1) K/odor... 4-(4-ethylbenzyl) -2-U·methoxy-D-glucopyrano-yl)-5-methyl-benzene 124938.doc -63 - 200829258

(2) 1-溴-2-(4-乙基苄基）-4-(1-甲氧基-D-葡萄糖哌喃-基）-6-甲基-苯(2) 1-Bromo-2-(4-ethylbenzyl)-4-(1-methoxy-D-glucopyranyl-yl)-6-methyl-benzene

(3) 1->臭-2-(4-乙基节基）-4-(1-甲氧基-D-匍萄糖略喃-1 基）-5-甲氧基-苯(3) 1->Smelly-2-(4-ethylbenzyl)-4-(1-methoxy-D-glucopyran-1-yl)-5-methoxy-benzene

(4) 2-(4-乙基卞基）-4-(1-曱氧基-D-匍萄糖略喃-1-基）-5- 甲氧基-苯甲腈(4) 2-(4-Ethyl-decyl)-4-(1-decyloxy-D-guanosin-1-yl)-5-methoxy-benzonitrile

使用4-溴-2-(4-乙基-苄基）-5_甲氧基-苯甲腈作為起始物質。亦可使用2-(4 -乙基-卞基）-4 -破-5-甲氧基-苯甲赌作為 124938.doc -64- 2008292584-Bromo-2-(4-ethyl-benzyl)-5-methoxy-benzonitrile was used as the starting material. It is also possible to use 2-(4-ethyl-indenyl)-4-broken-5-methoxy-benzoic bet as 124938.doc -64- 200829258

起始物質。實例XIV 0〆Starting material. Example XIV 0〆

〇'、丫、〇 6-(4-乙基苄基）_2_甲氧基-‘（I-曱氧基-D-葡萄糖哌味-1β (1 基）_苯甲腈將冷卻至-78°C之iBuLi於戊烷（1 8.3 mL)中之1.7 Μ溶液逐滴添加至冷卻至-78°C之1-溴-4-氰基-5-(4-乙基-苄基）_3·甲氧基-苯（5.0 g)於己烷（40 mL)及THF(20 mL)中之溶液中。亦可使用nBuLi或sBuLi替代tBuLi。添加完成且攪拌15 min 後，經由轉移針添加冷卻至·78π22,3,4,6-__〇_(5Τ* 矽烷基）-D-葡萄糖哌喃酮（90%，7·9 g)於己烷（3〇 mL)中之洛液。在_70。(：下將所得溶液攪拌2 h且隨後緩慢溫至 ° _5°c。用於水（100 mL)中之1%乙酸中止該反應且將所得混。物用乙酸乙酯萃取。將合併之有機萃取物用鹽水洗滌且 • 乾煤蚊鈉）。移除溶劑後，將殘餘物溶解於甲醇（50 mL) 巾且用甲燒續酸（2.5 mL)處理以產生所要之更穩定變旋異構鍵。將溶液在5(rc下授拌且隨後藉由添加固體NaHc〇3 來中和。在減壓下移除溶劑且將殘餘物溶解於乙酸乙醋中。將有機溶液用水及鹽水洗務且乾燥（硫酸納）。移除溶劑後，藉由石夕膠層析法（二氯甲以甲醇1:〇_>2:w化粗產 124938.doc -65- 200829258 物。產量·· 0.5 g(理論值之7%) 可類似於實例XIV獲得以下化合物： (1) 2-環丁氧基-6-(4-乙基苄基）-4-(1-甲氧基-D-葡萄糖哌喃-1-基）-苯甲猜〇', 丫, 〇6-(4-ethylbenzyl)_2_methoxy-'(I-decyloxy-D-glucosamine-1β(1 yl)-benzonitrile will be cooled to -78 The 1.7 Μ solution of iBuLi in pentane (1 8.3 mL) was added dropwise to 1-bromo-4-cyano-5-(4-ethyl-benzyl)_3· cooled to -78 °C. Methoxy-benzene (5.0 g) in hexane (40 mL) and THF (20 mL). nBuLi or sBuLi can be used instead of tBuLi. After the addition is completed and stirred for 15 min, the cooling is added via a transfer needle to · 78π22,3,4,6-__〇_(5Τ* decyl)-D-glucoperanone (90%, 7·9 g) in hexane (3〇mL) in 洛液. 70. (The solution obtained was stirred for 2 h and then slowly warmed to _5 ° C. The reaction was quenched with 1% acetic acid in water (100 mL) and the mixture was extracted with ethyl acetate. The organic extract was washed with brine and dried with sodium sulphate. After removing the solvent, the residue was dissolved in methanol (50 mL) and treated with toluene (2.5 mL) to give the desired more stable. Heterogeneous bond. The solution was mixed at 5 (rc and then neutralized by the addition of solid NaHc〇3. Solvent and dissolve the residue in ethyl acetate. Wash the organic solution with water and brine and dry (sodium sulfate). After removing the solvent, by chromatography, dichloromethyl to methanol 1: 〇 >2:w crude yield 124938.doc -65- 200829258. Yield ·· 0.5 g (7% of theory) The following compounds can be obtained analogously to Example XIV: (1) 2-Cyclobutoxy-6- (4-ethylbenzyl)-4-(1-methoxy-D-glucopyran-1-yl)-benzoic

〇、、'丫、〇〇 (2) 6-(4-乙基苄基）-2-異丙氧基-4-(1-甲氧基-D-葡萄糖哌喃-1-基）-苯甲猜〇,, '丫,〇〇(2) 6-(4-ethylbenzyl)-2-isopropoxy-4-(1-methoxy-D-glucopyran-1-yl)-benzene A guess

〇、、丫、〇 (3) 2-乙氧基-6-(4-乙基苄基）-4-(1-甲氧基-D-葡萄糖哌喃-1-基）-苯甲猜 124938.doc -66- 200829258〇,,丫,〇(3) 2-Ethoxy-6-(4-ethylbenzyl)-4-(1-methoxy-D-glucopyran-1-yl)-benzophenone 124938 .doc -66- 200829258

(4) 6-(4-乙基节基）-4-(1-甲氧基-D-匍萄糖ϋ辰喃-1-基）-6- 甲基硫基-苯甲猜 S〆(4) 6-(4-Ethyl)-4-(1-methoxy-D-glucosinolate-1-yl)-6-methylthio-benzophenone S〆

〇、、、丫、〇〇 (5) 2-(4-乙基苄基）-4-(1-甲氧基-D-葡萄糖哌喃-1-基）-5- 甲氧基-苯甲腈〇,,,丫,〇〇(5) 2-(4-ethylbenzyl)-4-(1-methoxy-D-glucopyran-1-yl)-5-methoxy-benzene Nitrile

實例XV 124938.doc -67- 200829258Example XV 124938.doc -67- 200829258

1-溴_2_(4·乙基苄基）_4·(1-經基_2,3,4,6-四-〇-苄基_£^葡萄糖哌喃-1·基）-5-曱基-苯 Γ1-Bromo-2_(4.ethylbenzyl)_4·(1-trans-base_2,3,4,6-tetra-indole-benzyl-£^glucopyran-1-yl)-5-oxime Base-benzoquinone

將nBuLi於己烷（1〇· 5 mL)中之1·6 Μ溶液逐滴添加至冷卻至_78°C之4-溴_5-(4-乙基-苄基）-1-碘-2-甲基-苯（7〇 g)於 THF(70 mL)中之溶液中。在·78°〇下將所得溶液攪拌丄h 後，經由轉移針添加預先冷卻至-70°C之2,3,4,卜肆_〇_节基-D-葡萄糖哌喃酮（91 g)於四氫呋喃（3〇 mL)中之溶液。在-75 C下將所得溶液擾拌3 h後，隨後藉由添加nh4C1水溶液中止該反應。將所得混合物用乙酸乙酯萃取，將合併之萃取物用鹽水洗滌且乾燥（硫酸鎂）。移除溶劑後，藉由矽膠層析環己烧/乙酸乙醋4:1->1:1)純化殘餘物。產置· 7·5 g(理論值之54%) 貝瑨（ESI+) : m/z = 844/846 (Br) [M+NH4] + 可類似於實例χν獲得以下化合物··Add 1Bu 6 solution of nBuLi in hexane (1 〇·5 mL) dropwise to 4-bromo-5-(4-ethyl-benzyl)-1-iodine-cooled to _78 °C. 2-Methyl-benzene (7 〇g) in THF (70 mL). After the resulting solution was stirred at 78 ° C, 2h was added, and 2,3,4, dip_〇_--------glucanone (91 g) previously cooled to -70 ° C was added via a transfer needle. A solution in tetrahydrofuran (3 〇 mL). After the resulting solution was scrambled at -75 C for 3 h, the reaction was then stopped by adding an aqueous solution of nh4C1. The resulting mixture was extracted with EtOAc. EtOAc (EtOAc) After removal of the solvent, the residue was purified by chromatography eluting with hexanes / ethyl acetate 4: 1-> Production · 7·5 g (54% of theory) Begonia (ESI+): m/z = 844/846 (Br) [M+NH4] + The following compounds can be obtained similarly to the example χν··

(4乙基苄基）_4_(丨羥基_2,3,4,6_四七_ 糖派喃小基)-5-甲氧基韻 124938.doc -68- 200829258(4ethylbenzyl)_4_(丨hydroxy-2,3,4,6_tetrakis-7-glycanyl)-5-methoxy rhyme 124938.doc -68- 200829258

將仁溴-2-(4-乙基-苄基）巧_甲氧基-苯甲腈用作起始物貝亦可使用第二丁基鐘替代nBuLi以傳遞鐘化之糖苷配基或使用 iPrMgCl*LiCl、iPr2Mg*LiCl 或 nBU3MgLi 以得到鎂化之衍生物來進行有機金屬糖苷配基之產生；所有該等有機金屬物質均添加至葡糖酸内酯中以傳遞所要中間物。亦可使用2-(4-乙基-苄基）-4_碘_5_甲氧基_苯甲腈作為起始物質。The use of bromo-2-(4-ethyl-benzyl) methoxy-benzonitrile as a starting material can also be used to replace nBuLi with a second butyl group to deliver a galvanized aglycone or use iPrMgCl*LiCl, iPr2Mg*LiCl or nBU3MgLi is used to obtain a magnesia derivative for the production of an organometallic aglycone; all of these organometallic species are added to the gluconolactone to deliver the desired intermediate. 2-(4-Ethyl-benzyl)-4_iodo-5-methoxy-benzonitrile can also be used as a starting material.

實例XVIExample XVI

1-溴_3-(4_乙基苄基）_2_甲基_5_(2,3,4,6四乙醯基葡萄糖哌喃-1-基）-苯將1-溴-3-(4-乙基苄基）-5-(1-甲氧基_D_葡萄糖哌喃q· 基）-2-甲基-苯（4·2 g)及三乙基矽烷（3_5 mL)於二氯曱烷（3〇 mL)及乙腈（90 mL)中之溶液冷卻至_15。(：。隨後以使溶液 124938.doc -69- 200829258 溫度維持於-51以下之速率逐滴添加三氟化硼***錯合物 (2·1 mL)。在冰浴中將所得溶液再攪拌〇·5 h且隨後藉由添加石反酸氫納水溶液中止該反應。在室溫下將所得混合物攪拌0.5 h且隨後分離有機層且將水層用乙酸乙酯萃取。將合併之有機層用鹽水洗務且乾燥（硫酸納）。移除溶劑且將殘餘物溶解於二氯甲烷（5〇 mL)中。在冰浴中將所得溶液冷卻且相繼添加咄啶（4.0 mL)、乙酸酐（4·3 mL)及4-二甲胺基 °比唆（0.1 g)。在周圍溫度下將溶液攪拌1 h且隨後用二氯曱烧（100 mL)稀釋。將有機溶液用鹽酸（於水中i m〇1/L)洗務兩次且乾燥（硫酸鈉）。在減壓下蒸發溶劑後，將殘餘物自乙醇中再結晶。產量：2.7 g(理論值之53%) 質譜（ESI+) : m/z=636/638 (Br) [M+NH4] + 可類似於實例XVI獲得以下化合物： (1) 1-溴-4-(4-乙基苄基）-2-(2,3,4,6-四-〇-乙醯基-0_〇-葡萄糖°辰喃-1-基）-5·甲基-苯1-bromo-3-(4-ethylbenzyl)_2-methyl_5_(2,3,4,6-tetraethylphosphoniumpiperidin-1-yl)-benzene 1-bromo-3-( 4-ethylbenzyl)-5-(1-methoxy-D-glucosylpyridinyl)-2-methyl-benzene (4.2 g) and triethyldecane (3_5 mL) The solution in chlorodecane (3 〇 mL) and acetonitrile (90 mL) was cooled to _15. (:. Subsequently, a boron trifluoride etherate complex (2.1 mL) was added dropwise at a rate such that the temperature of the solution 124938.doc-69-200829258 was maintained at -51 or less. The resulting solution was stirred in an ice bath. The reaction was quenched by the addition of a solution of aqueous sodium sulphate, and the mixture was stirred at room temperature for 0.5 h and then the organic layer was separated and the aqueous layer was extracted with ethyl acetate. Washed and dried (sodium sulphate). The solvent was removed and the residue was dissolved in dichloromethane (5 mL). The obtained solution was cooled in ice bath and acridine (4.0 mL), acetic anhydride (4) · 3 mL) and 4-dimethylamino group 唆 (0.1 g). Stir the solution at ambient temperature for 1 h and then dilute with dichlorohydrazine (100 mL). Use organic solution with hydrochloric acid (in water) 〇 1 / L) Washing twice and drying (sodium sulfate). After evaporation of solvent under reduced pressure, the residue was recrystallized from ethanol. Yield: 2.7 g (53% of theory) Mass Spectrum (ESI+): m /z=636/638 (Br) [M+NH4] + The following compounds can be obtained analogous to the example XVI: (1) 1-bromo-4-(4-ethylbenzyl)-2-(2,3,4 ,6 -tetrakis-acetamido-0-oxime-glucose ketone-1-yl)-5-methyl-benzene

〇八r 〇質譜（ESI + ) ·· m/z=636/638 (Br) [M+NH4] + (2)1-溴_2-(4-乙基苄基）-4-(2,3,4,6-四-0-乙醯基4_〇_葡萄糖哌喃-1-基）-6-曱基-苯 124938.doc -70- 200829258〇8r 〇 mass spectrometry (ESI + ) ·· m/z=636/638 (Br) [M+NH4] + (2) 1-bromo-2-(4-ethylbenzyl)-4-(2, 3,4,6-tetra-O-acetylindolyl 4_〇_glucopyran-1-yl)-6-mercapto-benzene 124938.doc -70- 200829258

質譜（ESI + ) : m/z=636/638 (Br) [M+NH4] + (3)1-溴-2-(4-乙基苄基）-4-(2,3,4,6-四-0-乙醯基1-0-葡萄糖哌喃-1-基）-5-甲氧基-苯Mass Spectrum (ESI + ) : m/z = 636 / 638 (Br) [M+NH4] + (3) 1-bromo-2-(4-ethylbenzyl)-4-(2,3,4,6 -tetra-O-acetamido 1-0-glucopyran-1-yl)-5-methoxy-benzene

〇質譜（ESI + ) : m/z=652/654 (Br) [M+NH4] + (4)6-(4-乙基苄基）-4-(2,3,4,6-四-0-乙醯基4-0-葡萄糖哌喃-1-基）-2-甲氧基·苯甲腈Rhodium mass spectrometry (ESI + ) : m/z = 652 / 654 (Br) [M+NH4] + (4) 6-(4-ethylbenzyl)-4-(2,3,4,6-tetra- 0-acetamido 4-0-glucopyran-1-yl)-2-methoxybenzonitrile

〇使用上述程序對6-(4-乙基苄基）-4-(1-曱氧基-D-葡萄糖 11 底喃-1-基）-2-甲氧基-苯甲猜進行遥原。 (5) 2·環丁氧基-6-(4-乙基苄基）-4-(2,3,4,6-四-0-乙醯基- 124938.doc -71 - 200829258 β-D-葡萄糖哌喃-1-基）-苯甲腈6 6-(4-Ethylbenzyl)-4-(1-decyloxy-D-glucos 11-endan-1-yl)-2-methoxy-benzophenone was subjected to the above procedure using the procedure described above. (5) 2·cyclobutoxy-6-(4-ethylbenzyl)-4-(2,3,4,6-tetra--0-ethenyl- 124938.doc -71 - 200829258 β-D -glucopyran-1-yl)-benzonitrile

〇使用上述程序對2 -環丁氧基- 6_(4-乙基节基）-4-(1-甲氧基-D·葡萄糖哌喃-1-基）-苯甲腈進行還原。 (6)2-(4-乙基苄基）-4-(2,3,4,6-四-〇-乙醯基-0-〇-葡萄糖娘喃-1-基）·5 -甲氧基-苯甲猜2 Reduction of 2-cyclobutoxy-6-(4-ethylbenzyl)-4-(1-methoxy-D-glucopyran-1-yl)-benzonitrile using the procedure described above. (6) 2-(4-Ethylbenzyl)-4-(2,3,4,6-tetra-indole-ethenyl-0-indole-glucose-1-yl)·5-methoxy Base-benzoic guess

使用上述程序對2-(4-乙基节基）-4-(1-甲氧基-D-動词糖哌喃-1-基）-5-甲氧基-苯甲腈進行還原。質譜（ESI+) : m/z = 599 [M+NH4] +The reduction of 2-(4-ethyl-benzyl)-4-(1-methoxy-D-verbosepiperan-1-yl)-5-methoxy-benzonitrile was carried out using the procedure described above. Mass Spectrum (ESI+): m/z = 599 [M+NH4] +

實例XVII 124938.doc -72- 200829258Example XVII 124938.doc -72- 200829258

1-溴-2-(4-乙基苄基）甲基_5_(2,3,4,6_四_〇_苄基·ρ-Ι)·葡萄糖哌喃-1-基）_苯在氬氣氛下將1-溴-2-(4-乙基苄基）-4-(1-羥基-D-葡萄糖底喃·1-基）-5-曱基-苯（7.5 g)及三乙基矽烷（7.3 mL)於二氯甲院（100 mL)中之溶液冷卻至·4(rc。隨後，以使溶液溫度維持於-30 C以下之速率逐滴添加三氟化硼***錯合物（3 .4 mL)。在_20°C下將所得溶液再攪拌2 h且隨後藉由添加碳酸氫鈉水溶液中止反應。分離有機層且將水層用二氯甲烷萃取。將合併之有機層用鹽水洗滌且乾燥（硫酸鎂）。移除溶劑且將殘餘物用5〇°c溫熱之乙醇處理丨0 min。藉由過濾分離不可溶剩餘物且用乙醇洗滌兩次。乾燥後產生標題化合物。產量：4.2 g(理論值之57%) 質譜（ESI+) : m/z=828/830 (Br) [M+NH4] + 可類似於實例XVII獲得以下化合物·· (1) 2-(4_乙基苄基）-4_(2,3,4,6_四_〇-苄基_3_0-葡萄糖哌喃-1-基）-5-甲氧基-苯甲腈 124938.doc -73 · 2008292581-bromo-2-(4-ethylbenzyl)methyl_5_(2,3,4,6-tetra-indole-benzyl·ρ-Ι)·glucopyran-1-yl)-benzene 1-Bromo-2-(4-ethylbenzyl)-4-(1-hydroxy-D-glucosyl-1-yl)-5-mercapto-benzene (7.5 g) and triethyl argon The solution of decane (7.3 mL) in dichloromethane (100 mL) was cooled to 4 (rc). Subsequently, boron trifluoride etherate complex was added dropwise at a rate to maintain the solution temperature below -30 C. (3.4 mL). The resulting solution was stirred for a further 2 h at -20 ° C and then quenched with aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with dichloromethane. Wash with brine and dry (magnesium sulfate). The solvent was removed and the residue was treated with warm ethanol for 5 min. The insoluble residue was separated by filtration and washed twice with ethanol. Yield: 4.2 g (57% of theory) Mass Spectrum (ESI+): m/z = 828 / 830 (Br) [M+NH4] + The following compounds can be obtained analogously to Example XVII (1) 2-( 4-ethylbenzyl)-4_(2,3,4,6-tetra-indole-benzyl-30.00-glucopyran-1-yl)-5-methoxy-benzene Formonitrile 124938.doc -73 · 200829258

使用上述程序對2_(4_乙基苄基）_4-(1-羥基-2,3,4,6_四_〇苄基葡萄糖哌喃基）-5_甲氧基_苯甲腈進行還原。Reduction of 2_(4-ethylbenzyl)_4-(1-hydroxy-2,3,4,6-tetra-indolylglucopyranosyl)-5-methoxy-benzonitrile using the above procedure .

實例XVIIIExample XVIII

NN

II 1〇^〇jXO^II 1〇^〇jXO^

1-氰基-3-(4-乙基苄基）-2_曱基_5-(2,3,4,6-四-〇_乙醯基_p一 D·葡萄糖派喃-1-基）_苯將燒瓶中裝入授拌棒、1·漠-3-(4-乙基苄基）-2-甲基_5_ (5 mg)、氰化辞（〇·2ΐ g)及四氟硼酸三第三丁基鱗（19 mg) 且置放於氬氣氛下。添加脫氣NMP(2 mL)且在室溫下將混合物攪拌1 6 h(或者，添加溶解於NMP中之起始糖普）。隨後，添加乙酸乙酯，過濾所得混合物且將濾液用NaHC〇3 水溶液洗滌。乾燥（硫酸鈉）有機溶液後，在減壓下移除溶 124938.doc -74- 200829258 劑且將殘餘物自乙醇中再結晶以產生純化之產物。產量：0.9 g(理論值之99%) 質譜（ESI+) : m/z=583 [M+NH4] + 可類似於實例XVIII獲得以下化合物： (1)1-氰基-4-(4-乙基苄基）-2-(2,3,4,6-四-〇-乙醯基-0-〇-葡萄糖哌喃-1-基）-5-甲基-苯1-cyano-3-(4-ethylbenzyl)-2_indolyl_5-(2,3,4,6-tetra-indole-ethenyl-p-D-glucopyran-1- Base)_Benzene was charged into the flask with a stir bar, 1 · desert-3-(4-ethylbenzyl)-2-methyl_5_ (5 mg), cyanide (〇·2ΐ g) and four Tri-tert-butyl fluoroborate (19 mg) was placed under an argon atmosphere. Degassed NMP (2 mL) was added and the mixture was stirred at room temperature for 16 h (or the initial sugar dissolved in NMP was added). Subsequently, ethyl acetate was added, the resulting mixture was filtered and the filtrate was washed with aqueous NaHCI. After drying the (sodium sulphate) organic solution, the solvent was removed under reduced pressure. 124938.doc-74-200829258 and the residue was recrystallized from ethanol to yield purified product. Yield: 0.9 g (99% of theory) Mass Spectrum (ESI+): m/z = 583 [M+NH4] + The following compounds were obtained in analogy to Example XVIII: (1) 1-cyano-4-(4-B Benzyl)-2-(2,3,4,6-tetra-indole-ethenyl-0-indole-glucopyran-1-yl)-5-methyl-benzene

〇 (2)1-氰基-2-(4-乙基苄基）-4-(2,3,4,6-四-〇-乙醯基-0-〇-葡萄糖哌喃-1-基）-5-甲基-苯〇(2)1-cyano-2-(4-ethylbenzyl)-4-(2,3,4,6-tetra-indole-ethenyl-0-indole-glucopyran-1-yl )-5-methyl-benzene

〇〇

實例XIX 〇人Example XIX 〇 people

〇〇

124938.doc -75- 200829258 1-氰基·2·(4_乙基节基）邻，3,4,6_四_〇乙醯基u葡萄糖哌喃-1-基）-6-甲基-苯124938.doc -75- 200829258 1-Cyano·2·(4_ethyl)yl, 3,4,6-tetra-indolyl u-glucopyran-1-yl)-6-methyl -benzene

將適合微波爐之容器中裝入基·4_(2,3,4,6—四-〇-乙醯基-β-D-葡萄糖哌味小基）_苯（0.2 g)、四水合氰化鎳（11)(40 mg)及NMp(05 mL)。在 2〇〇。〇下於微波爐中伴以攪拌將此混合物加熱9〇乙酸乙酯，過濾所得混合物且將濾液濃A suitable microwave oven is charged with a base of 4·(2,3,4,6-tetra-indolyl-β-D-glucosylpicuyl)-benzene (0.2 g), nickel cyanide tetrahydrate (11) (40 mg) and NMp (05 mL). At 2 〇〇. The mixture was heated in a microwave oven with stirring to 9 〇 ethyl acetate, and the resulting mixture was filtered and concentrated.

其在無需進一步純化之情況下經受全面去保護實例XX mil1。隨後，添加縮以得到粗產物，It was subjected to full deprotection Example XX mil1 without further purification. Subsequently, the addition is reduced to obtain a crude product,

2·(4·乙基节基）_S_甲氧基·4·(2,3,4,6_四乙醯基个萄糖旅味-1-基）-苯甲腈在215t下將裝有授拌棒、m♦乙基节基）甲氧基-4-(2,3,4,6-四-〇_乙醯基-p_D_葡萄糖哌喃基广苯〇羊6 g)、氰化銅（1)(0.56 g)&NMP(1〇 mL)之燒瓶攪拌3 h。隨後’添加水且藉由過濾、分離沈澱。將沈殿溶解於乙酸乙： (50 mL)中且經矽藻土過滤。將濾液乾燥（Na2s〇4)且濃縮了藉由石夕膠層析法(環己烷/乙酸乙酯2: Κ>1:2)純化殘餘物5。產量·· 1 · 1 g(理論值之75%) 質言晋（ESI+) : m/z=583 [M+NH4] + 124938.doc -76- 200829258 亦可使用實例XVI、XVIII及XIX所述之程序夢備物。2·(4·ethyl) _S_methoxy·4·(2,3,4,6_tetraethylene glucosylose-tele-l-yl)-benzonitrile will be packed at 215t There is a mixing rod, m♦ ethyl benzyl group) methoxy-4-(2,3,4,6-tetra-indole-ethylidene-p_D-glucopyranosyl broad benzoquinone 6 g), cyanide The flask of copper (1) (0.56 g) & NMP (1 mL) was stirred for 3 h. Water was then added and the precipitate was isolated by filtration. The sedum was dissolved in acetic acid B: (50 mL) and filtered through celite. The filtrate was dried (Na 2 s s 4) and concentrated to afford residue 5 by EtOAc (EtOAc/EtOAc: EtOAc: Yield·· 1 · 1 g (75% of theory) 质+(ESI+) : m/z=583 [M+NH4] + 124938.doc -76- 200829258 It can also be described using examples XVI, XVIII and XIX The program of dreams.

實例XXIExample XXI

1_>臭-2-(4-乙基苄基）-4-(择-0-葡萄糖旅味-1_基卜5_甲基_苯在周圍溫度下，將BC13於CH2C12(6.2 mL)中之i M溶液逐滴添加至1-溴-2-(4-乙基苄基）·5-甲基-4·(2,3,4,6-四-〇节基葡萄糖哌喃-1-基）-苯（ι·〇 g)及五甲基苯（24 於 CH2C12(25 mL)中之〉谷液中。添加完成後，在室溫下將溶液攪拌2 h。隨後，添加甲醇（5 mL)且將所得溶液再攪拌i 〇 min。在減壓下濃縮該溶液且藉由矽膠層析法（二氣甲院/甲醇1〇:1->3:1)純化殘餘物。產量：0·49 g(理論值之88%) 夤 ^(ESI ) : m/z=468/470 [M+NH4] + 可類似於實例XXI獲得以下化合物： (1) 2-(4-乙基苄基）-4-(p-D-葡萄糖旅喃-1_基）_5_甲氧基· 苯甲腈 124938.doc -77- 2008292581_>Smelly-2-(4-ethylbenzyl)-4-(selective-0-glucose travel--1_Kib5_methyl-benzene at ambient temperature, BC13 in CH2C12 (6.2 mL) The i M solution was added dropwise to 1-bromo-2-(4-ethylbenzyl)·5-methyl-4·(2,3,4,6-tetra-indenylglucopyran-1- Base) - Benzene (ι·〇g) and pentamethylbenzene (24 in CH2C12 (25 mL) in the solution. After the addition is completed, the solution is stirred at room temperature for 2 h. Subsequently, methanol is added (5 The resulting solution was stirred for an additional 〇 min. The solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography (di.sub.2 / methanol: </ RTI> 1-> 3:1). 0·49 g (88% of theory) 夤^(ESI): m/z=468/470 [M+NH4] + The following compounds can be obtained in analogy to the example XXI: (1) 2-(4-ethylbenzyl) Base)-4-(pD-glucose brimone-1_yl)_5_methoxy·benzonitrile 124938.doc -77- 200829258

〇質譜（ESI+) : m/z=431 [M+NH4] + 目標化合物之製備：實例1〇 Mass Spectrum (ESI+): m/z = 431 [M+NH4] + Preparation of target compound: Example 1

NN

〇 1_氰基-3-(4-乙基苄基）-5_(p_De>葡萄糖哌喃基）-2_曱基苯將氫氧化鈉水溶液（1 ·7 mL，4 mol/L)添加至溶解於甲醇 (6 mL)及THF(3 mL)中之1-氰基_3_(4_乙基苄基）-2-甲基巧_ (2,3,4,6-四乙醯基邛_〇•葡萄糖哌喃_卜基）_苯（ο.” g) 中。在至溫下將該溶液攪拌i h且隨後用鹽酸〇 m〇l/L)中和。移除有機溶織，將殘餘物用石炭酸氣納水溶液稀釋且，所得混合物用乙酸乙自旨萃取。乾燥（硫酸納）合併之有機萃取物且蒸發溶劑。藉切膠層析法（二氯甲謂醇ι:〇_ >8:1)純化剩餘物。產畺· 〇·45 g(理論值之75%) 貝清（ESI ) : m/z=4i5 [M+NH4] + 124938.doc •78- 200829258 可類似於實例1獲得以下化合物： (2) 1-鼠基-4-(4-乙基卞基）-2-(P_D-·萄糖略喃-1-基）-5· 甲基-苯〇1_Cyano-3-(4-ethylbenzyl)-5-(p_De>glucopyranosyl)-2-mercaptobenzene was added to aqueous sodium hydroxide (1·7 mL, 4 mol/L) to 1-cyano_3_(4-ethylbenzyl)-2-methyl _ (2,3,4,6-tetraethyl fluorenyl) dissolved in methanol (6 mL) and THF (3 mL) _〇•glucosinolate-b- phenyl)-benzene (ο.” g). The solution is stirred at room temperature for ih and then neutralized with 〇m〇l/L. The residue was diluted with an aqueous solution of sulphuric acid and the mixture was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and the solvent was evaporated. <RTI ID=0.0>;8:1) Purification of the residue. Calcium·〇·45 g (75% of theory) Beiqing (ESI): m/z=4i5 [M+NH4] + 124938.doc •78- 200829258 Example 1 The following compounds were obtained: (2) 1-Mercapto-4-(4-ethylindolyl)-2-(P_D-.glucopyran-1-yl)-5-methyl-benzene

〇、、、丫'〇〇 (3) 1-氣基-2-(4-乙基节基）-4-(p-D-fj萄糖派喃-1-基）-6_ 曱基-苯〇,,,丫'〇〇 (3) 1-Gasyl-2-(4-ethylhexyl)-4-(p-D-fj-glucopyran-1-yl)-6-decyl-benzene

〇、、丫、〇質譜（ESI + ) : m/z=415 [M+NH4] + (4) 2-(4·乙基苄基）-4-(P-D-葡萄糖哌喃-1-基）-5-甲氧基-〇, 丫, 〇 mass spectrum (ESI + ) : m/z = 415 [M+NH4] + (4) 2-(4-ethylbenzyl)-4-(PD-glucopyran-1-yl) -5-methoxy-

〇、、丫、〇質譜（ESI + ) : m/z = 43 1 [M+NH4] + 亦可如實例XXI中所述獲得該化合物。 (5) 6-(4-乙基卞基）-4-(β-0 -匍萄糖旅喃-1-基）-2 -甲乳基_ 124938.doc •79- 200829258 苯甲腈〇〆〇, 丫, 〇 Mass Spectrum (ESI + ): m/z = 43 1 [M+NH4] + This compound was obtained as described in Example XXI. (5) 6-(4-Ethyl decyl)-4-(β-0 - glucosin-2-yl)-2-methyllate _ 124938.doc •79- 200829258 benzonitrile 〇〆

〇、、、丫、〇質譜（ESI + ) : m/z=431 [M+NH4] +〇,,,丫, 〇 Mass Spectrum (ESI + ) : m/z=431 [M+NH4] +

(6) 2-¾ 丁氧基-6-(4-乙基卡基）-4-(β-ϋ-ιυ萄糖派喃-1-基）-苯曱腈(6) 2-3⁄4 Butoxy-6-(4-ethylcapto)-4-(β-ϋ-ι υ glucopyran-1-yl)-benzoquinone

〇、、丫、〇〇質譜（ESI·) : m/z=498 [M+HCOO]-實例7〇, 丫, 〇〇 Mass Spectrum (ESI·) : m/z=498 [M+HCOO]-Example 7

1-氮基_2-(4_乙基节基）-4-(p-D-葡萄糖旅味-1-基）·5_甲基-苯在220°C下於微波爐中將裝有攪拌棒、1-溴-2-(4-乙基苄基）-4-(P-D-葡萄糖哌喃-1-基）-5•甲基-苯（0.40 g)、Ni(CN)2 124938.doc •80- 2008292581-Nitro-2-(4-ethylphenyl)-4-(pD-glucosamine-1-yl)·5-methyl-benzene will be equipped with a stir bar in a microwave oven at 220 ° C. 1-Bromo-2-(4-ethylbenzyl)-4-(PD-glucopyran-1-yl)-5•methyl-benzene (0.40 g), Ni(CN)2 124938.doc •80 - 200829258

酸鈉）合併之有機萃取物且蒸發溶劑。藉由矽膠層析法（氯甲烧/甲醇1:0->8:1)純化剩餘物。產量：0.30g(理論值之85%) 質譜（ESI + ) ·· m/z=415 [M+NH4] + 實例8Sodium salt) combined organic extracts and evaporation of solvent. The residue was purified by silica gel chromatography (chloromethane / methanol 1:0 - > 8:1). Yield: 0.30 g (85% of theory) Mass Spectrum (ESI + ) ·· m/z = 415 [M+NH4] + Example 8

6-(4-乙基苄基）-4-(p-D-葡萄糖哌喃a·基）_2-異丙氧基_苯曱腈將1-氰基-6-(4-乙基苄基）-2-異丙氧基_4-(1-曱氧基七_葡萄糖哌喃-1-基）-苯（1.0 g)及三乙基矽烷（1〇 mL)於二氯甲烷（6 mL)及乙腈（8 mL)中之溶液冷卻至-2〇°C。隨後，以使溶液溫度維持於-l〇°C以下之速率逐滴添加三氟化硼*** 錯合物（0.7 mL)。經2 h之時間將所得溶液溫至且隨後藉由添加碳酸氫鈉水溶液中止該反應。在減壓下移除有機溶劑且將殘餘物用乙酸乙酯萃取。乾燥（硫酸鈉）合併之有機萃取物且移除溶劑。藉由逆相HPLC(YMC C 18，乙猜/ 水）純化殘餘物以得到純產物。產量：〇·1 g(理論值之10%) 124938.doc • 81 - 200829258 質譜（ESI + ) : m/z=459 [M+NH4] + 可類似於實例8獲得以下化合物： (9) 2-乙氧基·6-(4-乙基卞基匍萄糖派鳴-1 -基）· 苯甲腈6-(4-ethylbenzyl)-4-(pD-glucopyrane a.yl)_2-isopropoxy-benzonitrilecarbonitrile 1-cyano-6-(4-ethylbenzyl)- 2-isopropoxy- 4-(1-decyloxy-7-glucopyran-1-yl)-benzene (1.0 g) and triethyldecane (1 mL) in dichloromethane (6 mL) The solution in acetonitrile (8 mL) was cooled to -2 °C. Subsequently, a boron trifluoride diethyl etherate complex (0.7 mL) was added dropwise at such a rate that the temperature of the solution was maintained below -10 °C. The resulting solution was warmed up over 2 h and then quenched by the addition of aqueous sodium bicarbonate. The organic solvent was removed under reduced pressure and the residue was purified ethylamine. The combined organic extracts were dried (sodium sulfate) and the solvent was removed. The residue was purified by reverse phase HPLC (YMC C 18, EtOAc/water) to yield purified product. Yield: 〇·1 g (10% of theory) 124938.doc • 81 - 200829258 Mass Spectrum (ESI + ): m/z = 459 [M+NH4] + The following compound can be obtained similarly to Example 8: (9) 2 -ethoxy 6-(4-ethylindolyl glucosinolate-1 -yl)·benzonitrile

質譜（ESI + ) : m/z=445 [M+NH4] + (10) 6-(4-乙基卡基）-4-(p_D-葡祠糖旅喃-1-基）-2-甲基硫基-苯甲腈Mass Spectrometry (ESI + ) : m/z = 445 [M+NH4] + (10) 6-(4-ethylcarbyl)-4-(p_D-glucopyranol-2-yl)-2-methyl Thio-benzonitrile

質譜（ESI + ) ·· m/z=447 [M+NH4] + 實例11Mass Spectrum (ESI + ) ·· m/z=447 [M+NH4] + Example 11

OHOH

〇、、丫、0 〇 124938.doc -82- 200829258 6-(4-乙基苄基）-4-(p-D·葡萄糖哌喃-1-基）-2-羥基·苯甲腈在215它下將6-(4-乙基苄基）-2-甲氧基-4-(2,3,4,6-四-0-乙驢基-β-D·葡萄糖哌喃-^基）·苯甲腈（〇·36 g)及鹽酸吡錠 (0.72 g)之混合物加熱ι·5 h。冷卻至周圍溫度後，將混合物溶解於甲醇（8 mL)中且用4 M NaOH水溶液（2.5 mL)處理。在室溫下將該溶液攪拌1 h且隨後用鹽酸（4 mol/L)酸化。移除有機溶劑後，將殘餘物用乙酸乙酯萃取，乾燥 (硫酸納）合併之有機萃取物且蒸發溶劑。藉由逆相 HPLC(YMC C1 8，乙腈/水）純化剩餘物。產量：0·13 g(理論值之50%) 質譜（ESI+) : m/z=417 [M+NH4] + 可類似於實例11獲得以下化合物： (12) 2-(4-乙基卞基）-4-(p-D-葡萄糖略喃-1-基）-5-經基_苯曱腈〇,,丫,0 〇124938.doc -82- 200829258 6-(4-ethylbenzyl)-4-(pD·glucopyran-1-yl)-2-hydroxybenzonitrile at 215 6-(4-Ethylbenzyl)-2-methoxy-4-(2,3,4,6-tetra--0-ethenyl-β-D·glucopyran-yl)·benzene A mixture of carbonitrile (〇·36 g) and pyridinium hydrochloride (0.72 g) was heated for 5 h. After cooling to ambient temperature, the mixture was dissolved in EtOAc (EtOAc)EtOAc. The solution was stirred at room temperature for 1 h and then acidified with hydrochloric acid (4 mol/L). After the organic solvent was removed, the residue was extracted with ethyl acetate. The residue was purified by reverse phase HPLC (YMC C1 8. EtOAc/water). Yield: 0·13 g (50% of theory) Mass Spectrum (ESI+): m/z = 417 [M+NH4] + The following compound was obtained in analogy to Example 11: (12) 2-(4-ethyl fluorenyl) )-4-(pD-glucopyran-1-yl)-5-carbyl-benzoquinone

質譜（ESI+) : m/z=417 [M+NH4] + 亦類似於上述實例及自文獻中已知之其他方法製傷以下化合物： 124938.doc -83- 200829258Mass Spectrometry (ESI+): m/z = 417 [M+NH4]+ The following compounds were also similar to the above examples and other methods known in the literature: 124938.doc -83- 200829258

124938.doc -84- 200829258124938.doc -84- 200829258

現將描述調配物之一些實例，其中術語’’活性物質”表示一或多種本發明之化合物，包括其鹽。在與先前所述之一種或其他活性物質之組合中之一者的情況下，術語’’活性物質’’亦包括其他活性物質。Some examples of formulations will now be described, wherein the term ''active substance') means one or more compounds of the invention, including salts thereof, in the case of one of the combinations with one or the other of the previously described active substances, The term ''active substance'' also includes other active substances.

實例A 含有100 mg活性物質之鍵劑組成： 124938.doc -85- 200829258 1個錠劑含有：活性物質 100.0 mg 乳糖 80.0 mg 玉米澱粉 34.0 mg 聚乙烯°比洛咬酮 4.0 mg 硬脂酸鎂 2.0 mg 220.0 mg 製備方法：將活性物質、乳糖及澱粉一起混合且用聚乙烯吡咯啶酮水/谷/夜均勻濕/閏。師檢潮濕組合物（2·〇 mm之篩孔尺寸）且在50t：下於托架型乾燥器中乾燥後，將其再次篩檢（15 mm之篩孔尺寸）且添加潤滑劑。壓縮所完成之混合物以形成錠劑。旋劑重量：220 mg 直徑：10 mm，雙平面，兩側均磨成面且一側刻槽。實例B 含有15 0 m g活性物質之鍵劑細 ιΑί ! 1個錠劑含有：活性物質 150.0 mg 粉末狀乳糖 89.0 mg 玉米澱粉 40.0 mg 膠態二氧化矽 10.0 mg 聚乙烯σ比嘻咬ig 10.0 mg 124938.doc 86 200829258 硬脂酸鎖 1.0 rng 3 00.0 g 製備：將與乳糖、玉米殿粉及二氧化石夕混合之活性物質用2〇0/〇聚乙稀°比嘻σ定酮水溶液濕潤且穿過具有1 · 5 rnm之筛孔尺寸之篩網。將顆粒在45°C下乾燥，再次穿過同一筛網且與指定量之硬脂酸鎂混合。自該混合物壓製錠劑。Example A Composition of a bond containing 100 mg of active substance: 124938.doc -85- 200829258 1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyethylene ° pirone 4.0 mg magnesium stearate 2.0 Mg 220.0 mg Method of preparation: The active substance, lactose and starch are mixed together and uniformly wet/twisted with polyvinylpyrrolidone water/valley/night. After the wet composition (2·〇 mm mesh size) was examined and dried in a tray type dryer at 50 t:, it was again screened (15 mm mesh size) and a lubricant was added. The finished mixture is compressed to form a tablet. Rotating agent weight: 220 mg Diameter: 10 mm, double plane, both sides are ground and one side is grooved. Example B A key agent containing 150 mg of active substance fine ιΑί ! 1 lozenge contains: active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal cerium oxide 10.0 mg polyethylene σ ratio bite ig 10.0 mg 124938 .doc 86 200829258 Stearic acid lock 1.0 rng 3 00.0 g Preparation: The active substance mixed with lactose, corn powder and dioxide dioxide is moistened with an aqueous solution of 2〇0/〇polyethylene. Pass through a screen with a mesh size of 1 · 5 rnm. The granules were dried at 45 ° C, passed through the same screen again and mixed with the indicated amount of magnesium stearate. The tablet is compressed from the mixture.

錠劑重量：300 mg 模具：10 mm，平坦。Tablet weight: 300 mg Mold: 10 mm, flat.

實例C 含有150 mg活性物質之硬明膠膠囊組成：Example C Hard gelatin capsules containing 150 mg of active substance Composition:

1個膠囊含有：活性物質玉米澱粉（經乾燥）約乳糖（粉末狀約硬脂酸鎖約製備：將活性物質與賦形劑混合寸之篩網且使用合適裝置均 1號硬明膠膠囊。 150.0 mg 180.0 mg 87.0 mg 3.0 mg 420.0 mg 穿過具有0.75 mm之篩孔尺混合。將完成之混合物裳入膠囊填充：約320 mg 膠囊殼：1號硬明膠膠囊。 124938.doc -87- 2008292581 capsule contains: Active material corn starch (dried) About lactose (powder about stearic acid lock preparation: Mix the active substance with excipients in a sieve and use a suitable device for hard gelatin capsule No. 1 150.0. Mg 180.0 mg 87.0 mg 3.0 mg 420.0 mg Mix through a 0.75 mm mesh ruler. Place the finished mixture into a capsule filling: approx. 320 mg Capsule shell: No. 1 hard gelatin capsule. 124938.doc -87- 200829258

實例D 含有150 mg活性物質之栓劑組成· 1個栓劑含有：活性物質聚乙二醇1500 聚乙二醇6000 聚氧乙烯脫水山梨糖醇單硬脂酸酯 150.0 mg 550.0 mg 460.0 mgExample D Suppositories containing 150 mg of active substance Composition · 1 suppository containing: Active substance Polyethylene glycol 1500 Polyethylene glycol 6000 Polyoxyethylene sorbitan monostearate 150.0 mg 550.0 mg 460.0 mg

840.0 mg 製備： 2,000.0 mg _將检劑基㈣融後’使活性物質均句分布於其中且將炼融物傾入冷模型中。 '840.0 mg Preparation: 2,000.0 mg _ After the test substrate (4) is thawed, the active substance is evenly distributed and the smelt is poured into a cold model. '

實例E 含有10 mg活性物質之安瓶組成： 10.0 mg 2.0 ml 活性物質 0 · 01 N鹽酸適量重蒸餾水製備：將活性物質溶解於必要量之〇.〇丨N HC1中，用食鹽使其等滲，無菌過濾且轉移至2 ml安瓿中。Example E An ampule containing 10 mg of active substance: 10.0 mg 2.0 ml Active substance 0 · 01 N hydrochloric acid Suitable amount of distilled water Preparation: Dissolve the active substance in the necessary amount of 〇N 11 HC1 and make it isotonic with salt Filter sterile and transfer to 2 ml ampoules.

實例F 含有50 mg活性物質之安瓶組成： 124938.doc -88- 200829258 活性物質 50.0 mg 0.01 N鹽酸適量重蒸餾水至 10.0 ml 製備：用食鹽使其將活性物質溶解於必要量之0.01 N HC1中等滲，無菌過濾且轉移至10 ml安瓿中。 124938.doc -89-Example F Ampoule composition containing 50 mg of active substance: 124938.doc -88- 200829258 Active substance 50.0 mg 0.01 N hydrochloric acid q.s. distilled water to 10.0 ml Preparation: Dissolve the active substance in the necessary amount of 0.01 N HC1 with salt Permeate, sterile filtration and transfer to 10 ml ampoules. 124938.doc -89-

Claims

200829258 十、申請專利範圍：之苄基笨甲腈衍生物，其具有 1 · 一種經葡萄糖派喃基取代通式I :200829258 X. Patent application scope: A benzylic carbonitrile derivative having 1 · a substitution with a glucosyl group of the formula I:

其中： R2 表示氣、氯、漠、碘、C“烷基、c2_6烯基、 c2-6炔基、C3_7環烷基、Cw環烷基_c"烷基、羥基、Cl·4烷氧基、C3-7環烷基氧基、Cq 環烯基氧基、C1·4烷基硫基、胺基、硝基或氰基，门時以上k及之烧基-、稀基-、炔基-、環炫基-及環烯基-殘基可經氟單或多取代及/或經相同或不同取代基L2單或雙取代，且同時在以上提及之C5_6環烷基及c5_6環烯基環中’ 1或2個亞曱基可彼此獨立地經〇、s、 CO、so或so2置換，且 R 表示氫、氟、氯、溴、碘、Cw烷基、C2-6炔基、C2-6細基、C3-7環烧基、C3-7環烧基- Cl-3 烧基、C5-7環烯基、C5_7環稀基-Ci_3院基、芳基、雜芳基、Cw烷基羰基、芳基羰基、雜芳基羰基、胺基羰基、Cp4烷基胺基羰基、 124938.doc 二（C!·3烷基）胺基羰基、吡咯啶-1-基羰基、哌啶-1-基羰基、嗎啉-4-基羰基、哌嗪-1-基獄基、4-((^-4烧基）娘嗓-1-基毅基、經基罗炭基、Cw烷氧基羰基、Cw烷基胺基、二（cle3 烧基）胺基、吼洛唆-1 -基、旅咬-1 -基、嗎琳· 4-基、哌嗪-1-基、‘（Cw烷基）哌嗪-1-基、 Cl·4烧基魏基胺基、芳基魏基胺基、雜芳基癸炭基胺基、C 1.4烧基績酿基胺基、芳基續酸基胺基、CN6烷氧基、c3_7環烷基氧基、c5_7 環烯基氧基、芳基氧基、雜芳基氧基、CK4 烷基硫基、CN4烷基亞磺醯基、Cw烷基磺醯基、Cm環烷基硫基、c3-7環烷基亞磺醯基、 C：3·7環烷基磺醯基、c%7環烯基硫基、〇：5_7環知基亞％酿基、C 5-7環稀基績S藍基、芳基硫基、芳基亞續醯基、芳基績驢基、雜芳基硫基、雜芳基亞磺醯基、雜芳基磺醯基、胺基、經基、氣基及确基，同時以上提及之烷基-、烯基-、炔基-、環烷基-及環烯基-殘基可經氟單或多取代及/或經相同或不同取代基L2單或雙取代，且同時在以上提及之Gw環烷基及c5-6環烯基環中’ 1或2個亞甲基可彼此獨立地經〇、s、 C0、so或so2置換，且同時在以上提及之N-雜環烷基環中，i個亞曱 200829258 R4、R5 基可經CO或so2置換，且彼此獨立地表示氫、氟、氯、溴、碘、氰基、硝基、Cl·3烷基、Cw烷氧基、或經1至3 個氟原子取代之甲基或曱氧基， L1 係彼此獨立地選自氟、氣、溴、碘、羥基、氰基、Cw烷基、二氟甲基、三氟甲基、c13 烷氧基、二氟甲氧基、三氟曱氧基、胺基、 Ci_3烧基-胺基及二（Ci3烷基）_胺基；且 L2 係彼此獨立地選自氟、氯、羥基、羥基-Ci-4 烧基、C〗-4烧氧基、三氟甲氧基、Cl_4烷氧基-C〗·4烷基、氰基、羥基羰基、4烷基）氧基幾基、胺基羰基、c14烷基、三氟甲基、胺基、Ci·4烷基-羰基胺基、Cl_3烷基-胺基及二（Cu烧基）-胺基；且 R6、R7a、 R7b、R7c 彼此獨立地具有選自氫、（C1-18烷基）羰基、 (Ci-u烷基）氧基羰基、芳基羰基及芳基_(ci3 烧基）-羰基之含義，同時芳基可經相同或不同基團L 1彼此獨立地單或雙取代；同時在以上基團之定義中提及之芳基係意謂可如定義取代之苯基或萘基；且同時，除非另外說明，否則以上提及之烷基可為直鏈或支鏈，包括其互變異構體、立體異構體或其混合物，及其生 124938.doc .q. 200829258 理學上可接受之鹽。 2.如請求項1之經葡萄糖哌喃基取代之苄基-苯〒腈衍生物，其特徵在於R2表示氟、氯、溴、氰基、Cl 4烧基、 Cw烷基氧基、Cm環烷基、C3·7環烷基氧基或Cl_3烧基硫基’同時在C5·6環烧基環中，亞甲基可經〇置換，且其中任何烷基或環烷基環可經單或多氟化及/或經相同或不同之取代基L2單或雙取代，其中L2係如請求項1中所定義。 3 ·如請求項1或2之經葡萄糖哌喃基取代之苄基_苯曱腈衍生物，其特徵在於R3表示氯、溴、碘、Cw烷基、（^7環烧基、羥基、Cw烷基氧基、CP環烷基氧基、Cl_4烧基硫基、C3 -7 $衣烧基硫基’同時在C5 -6壤烧基環中，亞甲美可經〇置換，且其中任何烷基或環烷基環可經單或多氣化及/或經相同或不同之取代基L2單或雙取代，其中乙2係如請求項1中所定義。 4·如請求項1或2之經葡萄糖哌喃基取代之苄基-苯甲腈衍生物，其特徵在於R6表示氫、（Cw烷基）氧基羰基、Cl8燒基幾基或苯甲醯基且R7a、R7b、R7。彼此獨立地表示氫、 (C!·8烷基）氧基羰基、（Clj烷基）羰基或苯甲醯基。 5 ·如請求項4之經葡萄糖哌喃基取代之苄基·苯甲猜衍生物，其特徵在於R6、R7a、R7b、R7e表示氫。 6. 一種如請求項1至5中任一項之化合物之生理學上可接受之鹽，其係與無機酸或有機酸形成之鹽。 7· 一種醫藥組合物，其包含如請求項1至5中任一項之化人 124938.doc 200829258 物或如請求項6之生理學上可接受之鹽，視情況連同一或夕種t月性载劑及/或稀釋劑。 8. -種至少-種如請求項⑴中任—項之化合物或如請求員6之生理學上可接受之鹽的用途，其係用於製備適於治療或預防可受抑制納依賴性葡萄糖共轉運體sglt影響之疾病或病狀之醫藥組合物。 9. -種至少一種如請求項⑴中任一項之化合物或如請求員6之生理學上可接受之鹽的用途，其係用於製備適於治療或預防一或多種代謝病症之醫藥組合物。、 10. 如請求項9之用途，其特徵在於該代謝病症係選自由以下各病症組成之群：1型及2型糖尿病、糖尿病併發症、弋射f·生g夂中母或酮病、反應性低血糖、高胰島素血症、葡萄糖代謝障礙、抗胰島素症、代謝症候群、不同起因 ^血脂異常、動脈粥樣硬化及相關疾病、肥胖、高血壓、慢性心臟衰竭、水腫及高尿酸血症。 U· 一種至少—種如請求項1至5中任—項之化合物或如請求項6之生理學上可接受之鹽的用途，其係、用於製備用以抑制鈉依賴性葡萄糖共轉運體8〇1^2之醫藥組合物。 12. 一種至少—種如請求項1至5中任-項之化合物或如請求項6之生理學上可接受之鹽的用途，其係用於製備用以預防胰腺β·細胞退化及/或用於改善及/或恢復胰腺β•細於功月b性之醫藥組合物。 13· 一種至少—種如請求項1至5中任—項之化合物或如請求項6之生理學上可接受之鹽的用途，其係用於製備用以 124938.doc 200829258 預防、減緩、延遲或治療有此需要之患者中歸因、脂肪異常積聚之疾病或病狀之醫藥組合物。；臟 14. 一種至少一種如請求項丨至5中任一項之化合物或如姓、項6之生理學上可接受之鹽的用途，其係用於製備=求劑及/或抗高血壓劑。 & 15 · —種製備如請求項1至5中任一項之化合物之方去发徵在於： ’ ’其特 a)使通式Π化合物：Wherein: R2 represents gas, chlorine, desert, iodine, C "alkyl, c2_6 alkenyl, c2-6 alkynyl, C3_7 cycloalkyl, Cw cycloalkyl _c" alkyl, hydroxy, Cl. 4 alkoxy , C3-7 cycloalkyloxy, Cq cycloalkenyloxy, C1-4 alkylthio, amine, nitro or cyano, the above k and the alkyl-, dilute-, alkynyl -, cyclohexyl- and cycloalkenyl-residues may be mono- or polysubstituted by fluorine and/or mono- or di-substituted with the same or different substituents L2, and at the same time in the above-mentioned C5_6 cycloalkyl and c5_6 cycloalkenene '1 or 2 fluorenylene groups in the base ring may be independently substituted with hydrazine, s, CO, so or so2, and R represents hydrogen, fluorine, chlorine, bromine, iodine, Cw alkyl, C2-6 alkynyl, C2-6 fine base, C3-7 cycloalkyl, C3-7 cycloalkyl-Cl-3 alkyl, C5-7 cycloalkenyl, C5-7 heterocyclic-Ci_3, aryl, heteroaryl, Cw Alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, Cp4 alkylaminocarbonyl, 124938.doc bis(C!.3 alkyl)aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidine -1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-yl-peptidyl, 4-((^-4 alkyl) 嗓-1--yi , via carbocarbon group, Cw alkoxycarbonyl group, Cw alkylamino group, bis(cle3 alkyl)amine group, indole-1 - group, brittle l-yl group, holly 4-yl, Piperazin-1-yl, '(Cw alkyl)piperazin-1-yl, Cl. 4 alkyl-Wikiylamine, aryl-Wilylamine, heteroarylcarbylamino, C 1.4 alkyl Alkylamino, aryl, carboxylic acid, CN6 alkoxy, c3-7 cycloalkyloxy, c5-7 cycloalkenyloxy, aryloxy, heteroaryloxy, CK4 alkylthio, CN4 alkylsulfinyl, Cw alkylsulfonyl, Cm cycloalkylthio, c3-7 cycloalkylsulfinyl, C: 3·7 cycloalkylsulfonyl, c% 7 cycloolefin Thiothio group, hydrazine: 5-7 cyclinyl amide, C 5-7 ring dilute base S blue group, aryl thio group, aryl sulfhydryl group, aryl fluorenyl group, heteroaryl thio group , heteroarylsulfinyl, heteroarylsulfonyl, amine, transradical, gas radical and exact group, and the alkyl-, alkenyl-, alkynyl-, cycloalkyl- and The cycloalkenyl-residue may be mono- or polysubstituted by fluorine and/or mono- or di-substituted with the same or different substituents L2, and at the same time the Gw cycloalkyl and c5-6 mentioned above '1 or 2 methylene groups in the cycloalkenyl ring may be independently substituted with hydrazine, s, C0, so or so2, and at the same time in the above-mentioned N-heterocycloalkyl ring, i Aachen 200829258 The R4, R5 groups may be replaced by CO or so2, and independently of each other represent hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, Cl.3 alkyl, Cw alkoxy, or 1 to 3 fluorine Atom-substituted methyl or alkoxy group, L1 is independently selected from the group consisting of fluorine, gas, bromine, iodine, hydroxyl, cyano, Cw alkyl, difluoromethyl, trifluoromethyl, c13 alkoxy, and Fluoromethoxy, trifluoromethoxy, amine, Ci_3 alkyl-amino and bis(Ci3 alkyl)-amino; and L2 are independently selected from fluorine, chlorine, hydroxyl, hydroxy-Ci-4 Alkyl, C -4-alkyloxy, trifluoromethoxy, Cl 4 alkoxy-C -4-alkyl, cyano, hydroxycarbonyl, 4 alkyl)oxy, aminocarbonyl, c14 a group, a trifluoromethyl group, an amine group, a Ci-4 alkyl-carbonylamino group, a Cl_3 alkyl-amino group, and a bis(Cu alkyl)-amine group; and R6, R7a, R7b, R7c are independently selected from each other. From hydrogen, (C1-18 alkyl)carbonyl, (Ci-ualkyl) The meaning of oxycarbonyl, arylcarbonyl and aryl-(ci3 alkyl)-carbonyl, while the aryl group may be mono- or disubstituted independently of each other via the same or different groups L 1 ; and in the definition of the above groups And an aryl group means a phenyl or naphthyl group which may be substituted as defined; and, at the same time, unless otherwise stated, the above-mentioned alkyl group may be straight-chain or branched, including its tautomer, stereoisomerism Body or a mixture thereof, and its birth 124938.doc .q. 200829258 a physiologically acceptable salt. 2. The benzyl-benzoquinone derivative substituted with glucose piperyl as claimed in claim 1, wherein R2 represents fluorine, chlorine, bromine, cyano, Cl 4 alkyl, Cw alkyloxy, Cm ring An alkyl group, a C3·7 cycloalkyloxy group or a Cl_3 alkylthio group 'in a C5·6 cycloalkyl ring, the methylene group may be substituted by hydrazine, and any alkyl or cycloalkyl ring may be subjected to a single Or polyfluorinated and/or mono- or di-substituted with the same or different substituents L2, wherein L2 is as defined in claim 1. 3. A benzyl-benzoquinone derivative substituted with glucose piperyl as claimed in claim 1 or 2, characterized in that R3 represents chlorine, bromine, iodine, Cw alkyl, (^7 cycloalkyl, hydroxy, Cw Alkyloxy, CP cycloalkyloxy, Cl 4 alkylthio, C 3 -7 $Cylthiol' simultaneously in the C5 -6 lovial ring, methylene can be replaced by hydrazine, and any of them The alkyl or cycloalkyl ring may be mono- or poly-vaporized and/or mono- or di-substituted with the same or different substituents L2, wherein B2 is as defined in claim 1. 4. As claimed in claim 1 or 2 A benzyl-benzonitrile derivative substituted with a glucose piperyl group, wherein R6 represents hydrogen, (Cw alkyl)oxycarbonyl, Cl8 alkyl or benzhydryl and R7a, R7b, R7. Independently from each other, represents hydrogen, (C..8 alkyl)oxycarbonyl, (Cljalkyl)carbonyl or benzhydryl. 5. The benzyl-benzophenone substituted by glucose piperidyl as claimed in claim 4. a derivative, characterized in that R6, R7a, R7b, R7e represent hydrogen. 6. A physiologically acceptable salt of a compound according to any one of claims 1 to 5, which is in the form of a mineral or organic acid. 7. A pharmaceutical composition comprising a human of any of claims 1 to 5, 124938.doc 200829258 or a physiologically acceptable salt of claim 6, optionally with the same or And the use of a compound of the formula A pharmaceutical composition suitable for the treatment or prevention of a disease or condition which may be affected by the inhibition of the sglt of the nano-dependent glucose co-transporter. 9. A compound according to any one of the claims (1) or the physiology of the requester 6 Use of a salt of a physiologically acceptable salt for the preparation of a pharmaceutical composition suitable for the treatment or prevention of one or more metabolic disorders. 10. The use of claim 9, characterized in that the metabolic disorder is selected from the following Group of illnesses: type 1 and type 2 diabetes, diabetic complications, sputum f, raw g 夂 mother or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolism disorders, insulin resistance, metabolic syndrome, Different causes ^ blood lipids , atherosclerosis and related diseases, obesity, hypertension, chronic heart failure, edema, and hyperuricemia. U. A compound of at least one of the items of claims 1 to 5 or the physiological condition of claim 6. The use of a salt of a physiologically acceptable salt for the preparation of a pharmaceutical composition for inhibiting a sodium-dependent glucose co-transporter 8〇1^2. 12. At least one species as claimed in claims 1 to 5 Use of a compound or a physiologically acceptable salt of claim 6 for the preparation of a compound for preventing pancreatic β-cell degeneration and/or for ameliorating and/or restoring the pancreas Sexual pharmaceutical composition. 13. Use of at least one compound of any one of claims 1 to 5 or a physiologically acceptable salt of claim 6, for use in the preparation of 124938.doc 200829258 for prevention, mitigation, delay Or a pharmaceutical composition for treating a disease or condition attributable to abnormal fat accumulation in a patient in need thereof. Dirty 14. Use of at least one compound according to any one of claims 5 to 5 or a physiologically acceptable salt of the first name, item 6, for the preparation of a preparation and/or antihypertensive Agent. <15> The preparation of a compound according to any one of claims 1 to 5 is carried out as follows: ''

其中： R1 表示氰基、氣或溴； R，表示Η、Ci.4烷基、（Cl-18烷基）羰基、（Cl, 烷基）氧基羰基、芳基羰基及芳基_((^」烷基）-羰基，其中該等烷基或芳基可經_素單或多取代； R8a、R8b、 R8c、R8d彼此獨立地具有上文及下文中關於基團R6、 R7a、R7b、所給出含義中之一者，或表示节基或烯丙基或RaRbReSi基團或縮酮或縮醛基團’尤其表示亞烷基或芳基亞烷基縮酮或縮酸基團’同時在各情況下兩個相鄰基團 124938.doc 200829258 R8a、R8b、r8c、R8d J幵y成衣狀矽烷基縮嗣、縮酮或縮駿基團或1，2-二（Cu烷氧基）_Wherein: R1 represents cyano, gas or bromine; R represents hydrazine, Ci.4 alkyl, (Cl-18 alkyl)carbonyl, (Cl, alkyl)oxycarbonyl, arylcarbonyl and aryl_(( ^"alkyl"-carbonyl, wherein the alkyl or aryl group may be mono- or polysubstituted by _; R8a, R8b, R8c, R8d, independently of one another, above and below with respect to groups R6, R7a, R7b, One of the meanings given, or means that a benzyl or allyl or RaRbReSi group or a ketal or acetal group 'in particular means an alkylene or arylalkylene ketal or a condensed group' In each case two adjacent groups 124938.doc 200829258 R8a, R8b, r8c, R8d J幵y garment-like alkyl hydrazine, ketal or shrink group or 1,2-di(Cu alkoxy) _

Ra、R1 1，2-二（C!·3烷基）_伸乙基橋，同時以上提及之伸乙基橋連同哌喃糖環之兩個氧原子及兩個相關碳原子一起形成經取代之二噁烷環，尤其為2,3-二曱基-2,3_:(Ci_3烷氧基^，斗·二噁烷環，且同時烷基、芳基及/或苄基可經鹵素或Ch烷氧基單或多取代，且同時苄基亦可經二（Cl·3烷基）胺基取代；且 Rc彼此獨立地表*Cl·4烷基、芳基或芳基_c^ 烧基，其中该等芳基或烧基可經_素單或多取代；同日守以上基團之定義中提及之芳基係意謂苯基或萘基’較佳為苯基； τ 、且其中基團…至R6、R7a、R7b、R7C係如請求項i中所定義；在路易斯酸（Lewis acid)或布忍斯特酸（Br0nsted acid) 。、在下與還原劑反應，同時使所存在之任何保護基同時或Ik後裂解；若在式π化合物中r1表示Ο或以，則在隨後之轉化巾，使Rl之個別自素原子經氰基置換；或 )使通式III化合物水解： 124938.doc 200829258Ra, R1 1,2-di(C!·3 alkyl)_extended ethyl bridge, while the above-mentioned extended ethyl bridge together with the two oxygen atoms of the pipetose ring and two related carbon atoms form a Substituted dioxane ring, especially 2,3-dimercapto-2,3_:(Ci_3 alkoxy^, piped dioxane ring, and at the same time alkyl, aryl and/or benzyl group may be halogen Or a Ch alkoxy group which is mono- or polysubstituted, and at the same time, the benzyl group may also be substituted with a di(Cl·3 alkyl)amino group; and Rc independently of each other is represented by a *Cl·4 alkyl group, an aryl group or an aryl group _c^ a group, wherein the aryl or alkyl group may be mono- or polysubstituted by _; the aryl group mentioned in the definition of the above group on the same day means phenyl or naphthyl 'preferably phenyl; τ, and Wherein the group ... to R6, R7a, R7b, R7C are as defined in the claim i; in the Lewis acid or Bronsted acid, react with the reducing agent at the same time, and at the same time Any protecting group is cleaved at the same time or after Ik; if r1 represents hydrazine or in the compound of formula π, then in the subsequent conversion of the towel, the individual atom of R1 is replaced by a cyano group; or) the compound of formula III is made water Solution: 124938.doc 200829258

其中 R8a、R8b、 R8C、R 義，但基團R8a、R 及R2至R5係如請求項 1中所定、R8c、R8d 中之至少-纟不表示氫以產生如請求項1之式I化合物，其中R6、Rh、R7b及R7。表示氫，且若需要，則藉由醯化作用使因此獲得之R0表示氫原子之式I化合物轉化為相應通式I之醯基化合物，及/或若必要，則使上述反應中所用之任何保護基裂解，及/或若需要，則將因此獲得之式I化合物解析為其立體異構體，及/或若需要，則將因此獲得之式I化合物轉化為其鹽。 16· 一種製備通式II化合物之方法：Wherein R8a, R8b, R8C, R are synonymous, but the groups R8a, R and R2 to R5 are as defined in claim 1, and at least - of R8c, R8d does not represent hydrogen to produce a compound of formula I as claimed in claim 1, Wherein R6, Rh, R7b and R7. Representing hydrogen, and if desired, converting the thus obtained compound of formula I wherein R0 represents a hydrogen atom to a mercapto compound of the formula I by deuteration, and/or if necessary, any of the reactions used in the above reaction The protecting group is cleaved and/or, if desired, the compound of formula I thus obtained is resolved to its stereoisomer, and/or the compound of formula I thus obtained is converted to its salt if desired. 16. A method of preparing a compound of formula II:

其中R1 表示氰基、氣或溴；表示H、Ci_4焼基、（Ci-18烧基）幾基、（Ci-18 炫基）氧基魏基、芳基幾基及芳基-(Ci.3烧基）-幾基’其中該等燒基或芳基可經鹵素單 200829258 或多取代； 8b R8a、R R 彼此獨立地具有關於基團r6、R7a、r7 7e 所給出含義中之一者或RaRbR^A 或表示节基或烯丙基 ^ 1基團或縮酮或缩醛其圍门士难憋基團，同時在月下兩個相鄰基團R8a、R8b、r8c R8d ^環狀石夕院基縮酮、縮鋼或縮越基團或之广糖環之兩個氧原子-起形成經取代，3_乳基二。惡烷環，尤其為2,3·二曱基· 2其3:m基m，4_二嚼烧環，且同時烧 =芳基及/或节基可經_素或Cw燒氧基單二：取代’且同時节基亦可經二I烧基) 月女基取代；且 Ra、R1 R彼此獨立主一 ^ … 地表不C丨-4烷基、芳基或芳基_Ci3 、元基同時該等烷基或芳基可經!|素單或多取代； / 同時以上基團之定# ^ Α ^ 疋義中提及之芳基係意謂苯基或萘基，較佳為苯基；且汉2至R6、R7a、R7b、R7c係如請求項1中所定義，：將可藉由鹵素·金屬交換或藉由在通式IV之鹵素_ 卞基本化σ物之石厌·鹵鍵中***金屬而獲得且視情況經隨後之金屬交換之有機金屬化合物(ν): 124938.doc 200829258Wherein R1 represents a cyano group, a gas or a bromine; and represents a H, a Ci_4 fluorenyl group, a (Ci-18 alkyl) group, a (Ci-18 decyl) oxy-wei group, an aryl group and an aryl group (Ci. 3 calcining)-peryl group wherein the alkyl or aryl group may be substituted by halogen monopoly 200829258 or polysubstituted; 8b R8a, RR independently of one another has one of the meanings given for the groups r6, R7a, r7 7e Or RaRbR^A or a sulfhydryl or acetal group or a ketal or acetal which is a heterosexual group, and at the same time two adjacent groups R8a, R8b, r8c R8d^ The two oxygen atoms of the ketal, the shrinkage steel or the shrinking group or the wide sugar ring of the Shixi compound are formed to form a substituted, 3-meryl group. An oxane ring, especially 2,3·dimercapto 2, its 3:m group m, 4_dh chewing ring, and simultaneously burning = aryl and / or alkyl groups can be oxidized by _ or Cw 2: Substituting 'and at the same time, the cleavage group can also be substituted by the divalent I). The Ra and R1 R are independent of each other. The surface is not C丨-4 alkyl, aryl or aryl _Ci3, Wherein the alkyl or aryl group may be mono- or polysubstituted by a compound; / at the same time, the aryl group mentioned in the above formula is a phenyl or naphthyl group, preferably Phenyl; and Han 2 to R6, R7a, R7b, R7c are as defined in claim 1 : : can be exchanged by halogen · metal or by the halogen _ 卞 in the general formula IV An organometallic compound (ν) obtained by inserting a metal into a halogen bond and optionally exchanged by a subsequent metal: 124938.doc 200829258

其中Hal表示ci、Br及I且R1表示CN、Cl或Br，且R2至R5 係如請求項1中所定義，添加至通式VI之葡糖酸内酯··Wherein Hal represents ci, Br and I and R1 represents CN, Cl or Br, and R2 to R5 are added to the gluconolactone of formula VI as defined in claim 1

其中 R8a、R8b、r8c、r Ik後在酸存在下，使所得加合物與水或醇R，_〇H反應，同時R，表示視情況經取代之Cl·4烷基，且視情況使在與R’表示Η之水的反應中所獲得之產物在隨後之反應中以醯化劑轉化為式Η之產物，其中R，表示（CMS烷基）羰基、烷基）氧基羰基、芳基羰基或芳基兴烷基卜羰基，其可如所指定經取代。 1 7 · —種化合物，其具有通式〗v ··Wherein R8a, R8b, r8c, r Ik are reacted with water or alcohol R, 〇H in the presence of an acid, and R represents a optionally substituted C 4 alkyl group, and optionally The product obtained in the reaction with R' represents water of hydrazine is converted into a product of the formula by a hydrating agent in a subsequent reaction, wherein R represents (CMS alkyl)carbonyl, alkyl)oxycarbonyl, aryl A carbonyl or arylalkylalkylcarbonyl group which may be substituted as specified. 1 7 · a compound having the general formula 〖v ··

氣或〉臭且基團其中Hal表示氯、溴或碘，Ri表示氰基、 R2及R5係如請求項1中所定義。一種化合物，其具有通式II : 124938.doc -10- 200829258Gas or > odor and group wherein Hal represents chlorine, bromine or iodine, Ri represents cyano, R2 and R5 are as defined in claim 1. a compound having the general formula II: 124938.doc -10- 200829258

定義 124938.doc -11 - 200829258 七、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明：八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：Definition 124938.doc -11 - 200829258 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best Chemical formula showing the characteristics of the invention:

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